Tolerance Troubles

[Not meant as a claim that science doesn’t know something. More of an admission that I don’t know some things, and a hope to be informed about them by someone who does.]

Everyone knows about tolerance. The first time you take heroin, you get really high. The second time you take heroin, you get slightly less high. The nth time you take heroin, you barely feel good at all – but if you stop taking heroin, then you feel miserable. Your body adjusts, the receptors desensitize, whatever.

This is so simple that it took me forever to ask the obvious next question – how come this doesn’t happen for everything else? Supposedly if you have ADHD you can just stay on Adderall forever. Nobody says “The first time you take Adderall you can concentrate really well, the second time you take it you’ll concentrate less well, and the nth time you take it you can barely concentrate better at all.”

The psychiatry textbooks contain a sentence or two saying that “some” patients “may” develop Adderall tolerance, but it’s not something that we’re trained to expect. There are a lot of anecdotal reports online, but there are also anecdotal reports of people who don’t develop any tolerance at all after years and years. Hmm.

Also, people who abuse Adderall develop tolerance all the time, and keep having to up the doses just like heroin abusers do. This is a little weird – my pet theory is that people only develop tolerance to drug effects that aren’t FDA-approved uses – though how your receptors know what the FDA says I haven’t quite figured out. More seriously, it may be an effect of method of use – taking a small amount daily versus snorting a large amount of crushed tablet whenever you feel like it. Or it may be that tolerance to euphoric effects is worse than tolerance to stimulant effects.

(This seems true in general – I get euphoric effects from caffeine when I drink it very rarely; if I drink it more often, the euphoria goes away and I just feel a little more awake. This is important since it suggests tolerance isn’t just your body metabolizing the drug better, but actually a matter of receptor-level action – something I think everyone agrees is true, but which it’s always nice to have independent confirmation for.)

Sometimes tolerance gets weird. Antipsychotics are supposed to block dopamine receptors. Too much dopamine can contribute to psychosis, but it can also screw up the basal ganglia’s modulation of movement and cause you to make repetitive jerking motions all the time. People who have been on antipsychotics for too long may remain protected from psychosis, but start making repetitive jerking movements in a way consistent with too much dopamine. The theory goes that the receptors involved in psychosis haven’t developed tolerance (for some reason), but the receptors involved in movement modulation have developed so much tolerance that they’ve overshot their baseline and become supersensitive to dopamine. So by taking a drug that lowers dopamine, you get higher dopaminergic effects. In the worst case scenario, you end up with a condition called tardive dyskinesia, which is permanent. The receptors stay supersensitive forever and you will always make repetitive jerking movements. If you stop the antipsychotic, that will just make it (temporarily) worse – now you have supersensitive dopamine receptors and you’re not blocking them, so that means lots of repetitive jerking movements.

In this case, giving someone a drug has caused them to develop not just tolerance but supertolerance, where they are permanently worse than before. It’s as if taking heroin for long enough made you permanently miserable.

…which actually isn’t totally hypothetical. Some percent of people who abuse opiates like heroin get what’s called a post-acute withdrawal syndrome (PAWS), meaning that they feel depressed for months or years after they stop using the opiates. I treated a patient like for a while. I tried pretty much every antidepressant on him without success. He was just miserable. He’d been clean for about six months and I told him that he might just have to wait it out – it usually goes away after a few months to a year or so.

There is a poorly-studied but anecdotally very helpful treatment for PAWS: low-dose naltrexone. Naively, this sounds like the stupidest possible thing to try. It’s an opiate antagonist, meaning that you’re taking somebody who is undersensitive to opiates and blocking the tiny number of functioning opiate receptors they already have. It should be the only thing capable of making this already bad condition worse. Yet people swear by it. The theory is supposed to be the tolerance reaction again. Your body reacts to this opiate-blocking agent by releasing more opiates. So we’re treating a condition in which drugs that increase opiates cause you to have fewer opiates, by giving you a drug that decreases opiates which will cause you to have more opiates. How annoying is that?!

(some people recommend that if you’re giving someone opiate painkillers, you can give them low-dose naltrexone at the same time to prevent development of tolerance. Giving someone an opiate and an opiate-blocker simultaneously seems kind of like the medical equivalent of digging holes and filling them back in again, but apparently it does something useful)

This means we have examples of all three of the following:

1. A drug that’s supposed to have effect X, and after a while it still has effect X (Adderall)
2. A drug that’s supposed to have effect X, but after a while it has no effect (heroin)
3. A drug that’s supposed to have effect X, but after a while it overshoots and has effect anti-X (Antipsychotics? Heroin? Naltrexone?)

You may notice that these are all three of the logical possibilities. So for example, if we gave someone a drug that was supposed to decrease anxiety, it might decrease anxiety, have no effect, or increase anxiety. If scientific hypotheses are about closing off parts of possibility-space, then the receptor sensitivity hypothesis isn’t doing a very good job.

But it’s actually worse than this, because I get the impression that different people will end up in different branches of this trilemma. Benzodiazepines are a special offender here. Some people can take Xanax once a day for anxiety, and it’s a perfect solution – it suppresses their anxiety, it never stops working, and they never become addicted – if twenty years later they get a good therapist who helps them treat their anxiety without drugs, they can stop the Xanax with just a couple of days of mild discomfort. Other people will lose all effect after a couple of weeks, up the dose, up the dose some more, and end up as total wrecks. I think this is much less common than most people say – my attending’s rule of thumb is “benzo tolerance develops for sleep but not anxiety” – but it certainly happens. And for that matter, I’ve met a few people who never seem to develop tolerance for benzodiazepine sleeping pills. You see this same pattern for opiates used as painkillers. I spent so many years confused about whether people develop tolerance to these or not, and my final conclusion is that some people do and some people don’t and if you try to find a coherent universal pattern here you will go insane.

And it’s actually worse than this. Drugs don’t just work differently in different people, sometimes the same person will cycle through totally different mechanisms of drug response. SSRIs have something called tachyphylaxis, where they’ll work really well for months and then suddenly stop working (the word means “fast protection”, ie you develop protection against the drug effects quickly). This is even more annoying than the other patterns – at least with heroin, it makes sense that the receptors will gradually lose their sensitivity. But here? In random people at random times, the drug just stops working suddenly. It might be after a month, it might be after a year, it might be after ten years. And then every so often you’ll try the drug again a decade later, and then it’ll work just fine. Why? Nobody knows.

Some skeptics have pointed out that this is exactly what you would expect if the drug had no real effect and it was just luck that people didn’t have depressive episodes while they were taking them, but we know SSRIs have some effect. And anyway, placebo tachyphylaxis isn’t any less weird than real tachyphylaxis.

One more weird thing: LSD users report very strong tolerance lasting about three days after a dose, to the point where a second dose the day after will do almost nothing. Rat experiments have shown this is definitely because of receptor downregulation and not just enzyme induction. Okay. But LSD is a pretty strong drug. If receptors are so down-regulated that you are essentially on negative one tabs of LSD, how are you remotely normal while the tolerance is in effect? Are people during their periods of LSD tolerance less crazy and creative than normal? What the heck is the 5-HT2A receptor even doing if decreased amounts of it sufficient to render LSD ineffective don’t have noticeable effects on consciousness?

This is my concern about naltrexone as well. Sometimes doctors give naltrexone to help with alcohol addiction, which usually works okay. The theory is that since naltrexone blocks opiates, and opiates power the endogenous reward system, alcohol will seem less rewarding. Fine. But shouldn’t everything seem less rewarding? I always worry that I’m just blocking my alcoholic patients’ ability to enjoy anything at all (of which enjoying alcohol is a subset), but that doesn’t seem to be how it works. This is about when I default to my theory of “receptors read the FDA labels for medications and make sure to only do what they’re supposed to”.

All of this annoys me for a few reasons.

First, psychiatry really doesn’t think about this enough (or sometimes at all). The pharmacology textbooks will tell you how effective a drug is, how long it lasts, how many side effects it has, et cetera, but not whether it’s going to produce tolerance or not. It’s mostly just assumed that it won’t.

Second, groups skeptical of psychiatry are always talking about tolerance and it’s hard to tell whether they’re right or wrong. For example, some people claim antidepressants cause tardive dysphoria – that like the antipsychotics that eventually give permanent repetitive jerking movements, antidepressants can make serotonin receptors permanently undersensitive (or something) and so make depression worse. Other people say that antipsychotics themselves can eventually screw up dopamine receptors in ways that make psychosis worse (though see here). My guess is that these problems don’t arise for most people, but I can’t explain why these things wouldn’t happen.

Third, I think something like this is involved in addiction. Addiction is highly genetic; some people can drink alcohol socially their entire lives and never become alcoholic; other people quickly get hooked. This seems related to the thing where some people are stable forever at their low dose of opiate painkiller, and other people quickly develop tolerance and need to keep increasing it. I’m sure there are other things involved in addiction, but this is probably one of them.

Fourth, how many interesting things are we missing because they’re stupid and make no sense? I don’t know who first discovered that low-dose naltrexone could help potentiate the effect of opiates, but there have got to be other things like that. Forcing your body to become more sensitive to its own chemistry seems like a good alternative to forcing more and more foreign chemicals into it.

Finally, the best drugs seem to be the ones we hesitate to use because they produce too much tolerance. Xanax, opiates, you name it. A version of Xanax that that didn’t produce any tolerance would be a holy grail of anxiety disorder pharmacology. Some way to switch off Xanax tolerance would be just as good.

And a tolerance-free version of heroin would be pretty interesting too – from a purely pharmacological perspective, of course.

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344 Responses to Tolerance Troubles

  1. Dave Kinard says:

    Psychiatry likes to act as if the brain is much more simple then it is. As you know, there are different receptor sub-types, which correspond to different neurons in different brain circuits. That changes firing rates, which have downstream effects on other things.

    There are homeostatic mechanisms, and things that change in response to perceived environmental changes. And there is all sort of feedback from other body systems, endocrinological, immunological, etc.

    Psychiatry’s marketing presents a simplified picture that suggests people know what’s going on a lot better then they do.

    I’m sure you know there’s all sorts of ideas about what causes the onset lapse with SSRIs (auto-receptor downregulation, hippocampal neurogenesis, HPA-recalibration, etc)

    And poopout has even more theories.

  2. Adrian says:

    1. Anti-depressants have their own Severe discontinuation syndrome / withdrawal.

    The web is full of anecdotal evidence, of very high quality. Just one website has around 7000 patient reports with full history ( Just reading some patient reports shows that some (many) people have catastrophic results when trying to stops these meds.

    This is also the experience in my practice, with almost 50% of patients going through severe withdrawal without extended multi year tapers.

    Akathisia and movement disorders seem to be a prevalent symptom in these patients, just like for antipsychotics.

    2. I’ve read what you write about Anxiety treatments in another post.

    It seems you are not doing differential diagnosis for Akathisia and Anxiety.

    Patients who don’t respond to CBT or have chronic “anxiety” are, in my experience, often patients with prior exposure to anti-depressant / benzo / neuroleptics and in withdrawal, showing tardive akathisia symptoms.

    I’m not seeing mild withdrawal symptoms. To the contrary, many seem protracted and quite severe.

  3. Uncle Ilya Kuriakin says:

    Romantic love is celebrated as an experience so euphoric as to be addictive, whose pursuit can become so obsessive as to be destructive.

    Thus in its practical effects, the romantic experience is effectively (for many people) an addictive meta-drug, whose short-term effects are irresistibly pleasurable, yet whose long term sequelae not uncommonly are unpleasant or even catastrophically harmful.

    An erudite and SJW-friendly meditation upon this theme is Amélie Oksenberg Rorty’s “Spinoza on the Pathos of Idolatrous Love and the Hilarity of True Love,” which is collected in Moira Gatens’ Feminist interpretations of Benedict Spinoza (Pennsylvania University Press, 2009).

    In essence, Amélie argues that our appetites eventually tire of idolatrous love, just as we eventually tire of gluttonous eating — or if not, the consequences are harmful — and yet we never tire of Spinoza’s hilarious love, from which (according to Spinoza) no harmful consequences can ever result, no matter how much we indulge our appetite for hilarity.

    On the other hand, Amélie Rorty is Richard Rorty’s ‘ex’; and doesn’t her essay read naturally as having been subtitled as follows?

    “Richard’s philosophy is pathetic; that’s why I divorced him.”

    Ouch … these philosophic waters get deep mighty fast, don’t they? 🙂

    The literature of hilarious SJW philosophy goes back to the 1980s, and yet only now is it receiving the mainstream philosophic attention that it deserves … concomitantly (and not coincidentally) with the increasingly solid foundations that the neuroanatomic, neurofunctional, and neurophysiologic literature supplies to hilarious cognition … the burgeoning STEAM-discipline of cognitive parcellation being of course intrinsically hilarious:

    Ethics Part III, Prop. XI  Whatsoever increases or diminishes, aids or restrains, the power of our body to act, in the same measure does the idea of the same thing increase or diminish, aid or restrain, the power of our mind to think.

    For further philosophical reading, works like Genevieve Lloyd’s “Rationalizing the Passions” (1989) are commended to SSC readers.

    Is hilarious cognition destined to become serious 21st century thing? The chief objective equally of post-rational SJW faith, mainstream psychiatric practice, and transformational technological illumination? The fulfillment of Baruch Spinoza’s 350 year-old  philosophical dreams?

    Yah, sure, you betcha … and you read it first, here on SSC! 🙂

  4. Utopn Naxl says:

    Oh, a slightly peeved skeptical comment. Not really skeptical of your post, just pharma in general.

    >Supposedly if you have ADHD you can just stay on Adderall forever.

    As kids, there are *at least* 2 days out of the week its not taken. As adults, its taken on a PRN basis, and far less often then coffee. Since really only adults can say how much different they feel on it with accuracy and precision and little kids have to just shut up and take it, I would say the results for kids are skewed.

    My guess for adults is that it helps a bit in setting up good habits, and then its more the habits that continues. For kids, a med that loses half of its effectiveness in three months might not even really be noticed.

    “The psychiatry textbooks contain a sentence or two saying that “some” patients “may” develop Adderall tolerance, but it’s not something that we’re trained to expect. ”

    Doesn’t that trigger some massive warning/bullshit flares? Why would people be so genetically different that these chemicals only give tolerance to some people and not others, at least in this way? If there is a “may” involved in this without further explanation, like say American Indians lack some genes to break down alcohol, something is really really bad (and that’s a terrible example , but the closest analogous explanation to what one would expect I can think of right now)

    > It’s mostly just assumed that it won’t.

    A great way to have permanent patients!

    • Uncle Ilya Kuriakin says:

      Not a cough in a carload … 🙁

      Most likely, our present pharmaceutic practices won’t look all that good in the light of future neurophysiological understanding.

      Still we must embrace the best medical practices that we presently can conceive, in the too-dim light of what we presently know and understand …

    • Protest Manager says:

      Doesn’t that trigger some massive warning/bullshit flares? Why would people be so genetically different that these chemicals only give tolerance to some people and not others, at least in this way?

      Um, because people are significantly genetically different from each other?

      Because all it takes is a point mutation in the gene for a receptor (or in any of the proteins the receptor triggers) to significantly change the way the receptor “behaves”?

      There’s a reason why I mentioned “pharmacogenomics” in the post right above yours. Look it up. Point mutations, let alone insertions, deletions, and duplications, can and do lead to changes that make the difference between life and death. The idea that they can’t make a difference between tolerance and not, is just silly.

    • Rebecca Friedman says:

      Caffeine works differently on different people – some can’t sleep if they had it before bed, others can happily have a cup or two with dinner; some people get addicted, others don’t; some people get energized, others don’t*. I’m not sure it’s that farfetched to say that some drugs just do vary in effect based on ? traits (probably genetic) of the people taking them.

      Point taken about kids, though.

      *Me, so yeah, this one’s for real.

      • Utopn Naxl says:

        I think most variability in the perceived effects of it are due to factors such as these:
        People taking it with different foods(taking it with food and bread will have the caffeine given over the time of digestion of the bread,taking it injected into the arm will give different results), giving the same amount to people with various body weights vastly changes what people think of it,as it appears that caffeine/kg of some sort of bodyweight function is much more predictive then overall caffeine,and also people having cups or two with dinner my bet is that they have developed some level of tolerance to it. And of course, there is the prior alertness level one has before they take it. At full alertness, or at fatigue level.

        Those daily differences in consumption can likely explain the bulk of perceived variability of effects.

        With the known corruptions in the medical industry, i am inclined to believe that a great deal of this “different tolerances for everyone” is merely the consequence of a profit-maximizing industry that knows it can get away with a good deal.

  5. Protest Manager says:

    Two thoughts:

    1: This looks like it could be an interesting intersection between pharmacogenomics and epigenetics. Especially with the people who see a rapid change in response.

    2: Instead of “receptors read the FDA labels for medications and make sure to only do what they’re supposed to”, how about “receptors don’t habituate when you’re doing what your’e supposed to do”?

    You’re “not supposed to be” euphoric all the time, so receptors adjust against it. You’re “not supposed to be” in agonizing pain, or totally dysfunctional, so receptors don’t “tolerate” when you’re taking opioids for actual pain, or Adderall for actual ADHD.?

  6. jordan says:

    Loved the original post and think this would be a great thing for us to understand more completely. Using food as an analogy, the caloric energy gained through consumption (at least to my knowledge/ according to our current theories) is not dependent on tolerance, time of day being consumed, social setting, time since last usage, etc). But the psychological effects (I haven’t experimented with nootropics, so I’m stuck with food people) vary greatly on all those factors, as well as on other things that I don’t understand.

    I doubt the caloric/ metabolic side of food is as simple as we often model it, but I also think the “simple tolerance” model that treats basically any mood altering substance as an inevitable dead end is false as well. There are relatively consistent effects regardless of tolerance as well as inconsistent effects dependent on general tolerance, time since last usage, etc. There is tolerance that happens permanently after one use, so that even ten years later without any use the drug or food will have a different effect than if you were a first time user, while there is other tolerance that is basically erased with the passage of time. Agreed, this stuff needs to be researched much more.

    But I think treating the mind and human emotions like happiness/ general anxiety independent of human life, socialization, and physical experience is probably not smart and seems to be a trend in psychopharmacology from what I’ve read. The goal of a permanent state of idle euphoria is not a goal most people would describe as “good” but rather as something akin to the matrix, and I think drugs should be treated as a means to an end. In other words, I think doctors should treat their patients to drugs in a way similar to Olympic coaches giving steroids to their team members (illegally)- rather than an internal goal of nirvana and inner peace, the goal should be something more substantial and idyllic, like a house with two kids, a dog, and a three goldfish or something. Nirvana and inner peace are goals that, even if we could achieve them with drugs and drugs alone, would not really contribute to the human experience (or to our ability to survive/ compete on an evolutionary level).

  7. Bram Cohen says:

    Your patient who has quit heroin but still has withdrawal symptoms might be an ideal candidate for ibogaine. Ibogaine has the remarkable property of somehow dodging the withdrawal symptoms of heroin and an, ahem, intense trip. The problem with it is that some people go back to using heroin afterwards. Someone who has reliably quit but is still experiencing withdrawal symptoms might find it miraculous.

  8. Jill says:

    Maybe research scientists and doctors need to try to “think outside the box” here, about not just what is happening with a treatment, but what is happening with an illness or symptoms. There is physical and/or emotional pain, and sometimes it’s hard to tell where one ends and the other begins, if indeed there is a clear separation.

    With symptom pictures where the person has muscle pain, sometimes doctors think it’s “all in the person’s head” because the tests don’t show a consistent picture, and the pain travels from one area of the body to another.

    But, as with fibromyalgia, some of the other symptom pictures too, may be ones where the origin of the pain is not dysfunction in a particular limb or other part of the body. Sometimes it’s general muscle weakness or fatigue– a situation where it’s easier than normal for the person to strain or sprain the muscle. So they strain/sprain one muscle, and then they start favoring the other arm or leg, and then they sprain that one. So the pain travels because the muscles are weak and easily fatigued and strained, and the person keeps switching to using the muscle that isn’t yet sprained/strained.

    In this case, you don’t try to specifically fix the limb it starts with, and then fix the next one they strain/sprain. You see if you can gradually increase muscle strength and resilience. So you try a very gradual exercise program to see if that helps, and it often does.

    With depression, you may sometimes have a similar picture. The person may not actually have a physiological depression you can fix. Or maybe they do, but maybe you can fix it without drugs. Maybe the person needs to become gradually more psychologically resilient. If they are capable of becoming gradually more emotionally resilient over time, certain types of psychotherapy can help them with that.

    I have relatives in another state who take drugs for anxiety, depression etc., mixed with a lot of alcohol. They just don’t believe in psychotherapy. And there’s nothing I can do to change their minds, because their psychiatrist doesn’t believe in it either, and they totally trust in him and believe every word that comes from his mouth.

    They misunderstand and misinterpret other people constantly, jumping to overly negative conclusions about the other people’s intentions or character. Small temporary misunderstandings of other people, turn into consistent evil intentions and character traits of those people, in their eyes.

    It’s easy for me to see, from the outside looking in, how they are constantly creating their own problems, and how they might benefit from psychotherapy if they were willing to go to it. Because they lack resilience, and they consistently sabotage themselves, and make their problems worse unnecessarily. It’s the psychological equivalent to beating your head against the wall, and then going to the doctor because your head hurts and it’s bleeding. And you have “tolerance” to the pain drugs– your head keeps hurting and bleeding when you hit it against the wall, even though you are on the drugs for pain.

    Of course there are the issues of exercising and eating sensibly too. Some people who have no resilience and/or a lot of physical and emotional pain could benefit from a better diet, not consuming tons of caffeine and/or alcohol etc.

    Perhaps some of the folks who develop tolerance to drugs could learn emotional resilience over time and not end up with “tolerance” to that resilience building program.

    I know that holistic medical people sometimes give supplements to people withdrawing from opiates or other substances, claiming that they are low in e.g. Vitamin B-12, or other vitamins or minerals, so that could be a factor too.

    Anyway, there are questions here for researchers and doctors, e.g.

    –Do I really understand what the symptoms are– in terms of whether this is more fatigue or lack of strength or resilience vs. more of a problem with fatigue, lack of strength, or lack of resilience?

    –Do I really understand what the effects of the drug are on the individual– as opposed to the average effect on individuals in the studies of the drug?

    • Uncle Ilya Kuriakin says:

      With her usual explicit empathy, Jill tells a too-familiar tale of tolerance:

      I have relatives in another state who take drugs for anxiety, depression etc., mixed with a lot of alcohol. […]

      They misunderstand and misinterpret other people constantly, jumping to overly negative conclusions about the other people’s intentions or character. Small temporary misunderstandings of other people, turn into consistent evil intentions and character traits of those people, in their eyes. […]

      It’s easy for me to see, from the outside looking in, how they are constantly creating their own problems, and how they might benefit from psychotherapy if they were willing to go to it.

      Jill’s description is familiar to anyone whose circles of family and friends tolerate longstanding toxic syndromes of personality disorder ⊗ alcohol ⊗ pills. Is this social / emotional / empathic tolerance any less crucial to psychiatric practice than pharmaceutical tolerance?

      Many cultures have the saying “The man takes a drink; the drink takes a drink; the drink takes the man”; not uncommonly this progression-of-tolerance is seen, nowadays, with psychiatric medications too.

      Yet psychotherapy has spawned (as far as I can appreciate) no comparable culturally universal sayings, has it? It’s natural to wonder why not, isn’t it? Here Spinoza’s hilaritas springs to mind as the central goal of psychotherapy:

      The elusive state of hilaritas — of which, if only we can get it at all, we cannot get too much.

      Hmmm … a persistent state of hilaritas could be mighty addictive, couldn’t it? 🙂

      This is not to assert that psychotherapy is any kind of panacea (any more than Spinoza’s hilaritas is a philosophical panacea) but rather to reflect (soberly) that medical practice (and especially psychiatric practice) remains regrettably in a dark age:

      Medicine is of all the Arts the most noble; but, owing to the ignorance of those who practice it, and of those who, inconsiderately, form a judgment of them, it is at present far behind all the other arts.
           —Hippocrates circa 370 BC.

      In too many medical respects, not much has changed in the  two+ millennia since Hippocrates summarized the state of his art … and yet, we may hope for great advances, and soon! 🙂

  9. Joscha says:

    We already know that there are multiple independent systems that use dopamine, serotonin etc. as their signaling chemical, and these systems have different setpoints. By changing the global level, we are affecting these systems in different ways in different people.

    Now what if within each system, there are effect and control subsystems? The effect subsystem uses the respective chemical for regulating the desired function, while the control subsystem monitors the effect subsystem and makes sure that diet, metabolism, aging do not push it out of the useful range? Bipolar conditions could be defects in the secondary regulation, which lets the system over- and undershoot the good ranges. Likewise, the secondary system has its own receptors for the respective chemical, and your opiate blocker could act more on the control system, thereby causing it to fail to sense the presence of opiates, and thereby increasing the sensitivity of the primary system. It could even be that the sensitivity regulation happens post-receptor in the primary system, i.e. you get the effect of the opiates with fewer or perhaps even no opiates, by affecting the neurons downstream of the receptor neurons.

  10. Deiseach says:

    Uh, Scott, what was that you were saying about Elderly Hispanic Women? 🙂

  11. Joyously says:

    Sometimes chocolate gives me euphoria and sometimes it just tastes good. I don’t know if it has to do with how much I’ve had lately, or where I am on my hormone cycle, or whatever, but it certainly feels like there’s a real chemical difference going on in my brain.

  12. Glen Raphael says:

    Huh. I just realized something. When I was a kid I’d get a cold and take Contact (which I think was mostly pseudophedrine?) to clear up my stuffy nose. It was ludicrously effective. I would quickly go from barely-able-to-breathe to perfectly able to breathe and stay almost painfully dry and cleared-up (and perhaps a bit groggy) for more or less the package-advertised amount of time (usually 12 hours).

    You know what drug has that effect for me now? ABSOLUTELY NONE. There is no drug I have found that clears up a stuffy nose today the way Contact did ~20 years ago. It’s not JUST that all the good stuff is now hidden behind the counter due to the War On Meth – even the stuff you sign and show your license for doesn’t really work either.

    I had not considered the possibility that I might have simply adapted to the usual kinds of cold medicine. Maybe I’ve become immune to that particular drug or that amount of it – the next time I have a cold or allergies I need to find different drugs or take larger doses to get the same sort of effect.

    • Doctor Mist says:

      Contac was big mojo, no question. I’m pretty sure this was before pseudoephredine. I remember that it included belladonna, which even as a kid I knew was a poison (this was before I learned that “the dose makes the poison”). A commenter on Straight Dope says “The old formula had phenylpropanolamine, chlorphenaramine maleate, and a bit of atropine and belladonna alkaloids. Phenylpropanolamine is a decongestant that reduces mucosal swelling, chlorphenaramine maleate is an antihistamine for runny nose and sneezing, and the belladonna parts also have a drying effect on the nasal mucosa.”

      • Glen Raphael says:

        Aha! Thank you for the pointer – adding “straight dope” to my searches found what I needed. PPA was used both as a decongestant and for weight loss. Primarily when used for weight loss (“Dexatrim”) that ingredient was linked to increased stroke risk for women (though not for men), so the FDA asked companies to “voluntarily” stop using it in 2000, judging that the risk exceeded the benefits.

        As a result of this change, the post-2000 Contac – even the one behind the counter – is indeed a completely different formula than the pre-2000 Contac.

        So I guess my followup question is: is there any OTC decongestant still remaining on the market that isn’t largely placebo? Anything that comes anywhere near how well Contac worked?

        (Because if not, I need to smuggle a personal supply back the next time I visit Europe.)

        • suntzuanime says:

          “Fuck the FDA for not letting me snort deadly nightshade”

          • Glen Raphael says:

            Pretty much, yeah. The FDA assigns approximately zero value to any drug benefits that aren’t literally lifesaving. But some people really need a decongestant that works for them. If there existed other drugs that did the same thing approximately as well only safer that would be one thing, but…there aren’t.

            If there’s a tiny increase in a tiny risk for a specific population, let the FDA put that on the warning label. Let them say “this product is not approved by the FDA, use at your own risk.”

            But no, I don’t grant the FDA the right to decide for me what risks are worth taking by me. FDA approval should be optional.

            And it looks like the brand names I seek are Respa-AR and Ru-Tuss. Which do indeed contain belladonna, but like they say: “the dose makes the poison”.

  13. christopher andrew upshaw says:

    “Nobody says “The first time you take Adderall you can concentrate really well, the second time you take it you’ll concentrate less well, and the nth time you take it you can barely concentrate better at all. ”

    They don’t? Because that is my experience with them, that I have only been able to deal with it by going from 5mg of stratera 120 mg + two cups of coffee a day.

  14. Miranda says:

    Anecdotally, the day after being on LSD does feel sort of like being on “minus X tabs of LSD”, at least in some ways, and definitely isn’t “normal consciousness”.

    I’m now trying to think of other examples of medicine that are sort of like digging holes and filling them in again. Having a patient on an epinephrine drip and giving them beta-blockers as well would be a pretty good example – and in fact I’ve never done that and a patient requiring an epi drip is a pretty good reason to hold their ordered beta blockers. But I have had patients on epi and amiodarone, an antiarrhythmic that slows heart rate and decreases blood pressure – opposite of epi. But they don’t have exactly opposite mechanisms of action, and the *purpose* of amio is to prevent lethal arrhythmias, not decrease blood pressure – you would usually prefer it not to do that. So you’re sort of working at cross-purposes but still getting something you care about.

    Treating rhabdomyolysis with fluids + diuretics might be another example.

  15. Prince Ali says:

    Fwiw, I notice definite changed in mood etc after coming down off LSD, that last for a short while. I perceive it as a certain calmness and centeredness and profound lack of interest in consuming drugs. I’ve always attributed it to the experience of the trip, but it could be receptors also.

  16. Jill says:

    The apparently very helpful treatment for PAWS, low-dose naltrexone, sounds like it increases the body’s own ability to produce opiates.

    It sounds like researchers aren’t yet looking so much at the separate categories of:

    1. What substances does this drug give/add to people’s bodies? If it does that, does it have the desired effects? For how long on average? For what percentage of people does it have the desired effects? For what percentage of people do the desired effects last for some minimum amount of time, without an increase in dosage?


    2. What substances does this drug stimulate the body to produce on its own? If the drug does this, how long does it do that? Does the drug have the desired effects? For how long? And do the effects stop once the drug is discontinued? Or does the drug jump start the body’s capacity to produce the substance, so that a person need only take the drug temporarily?– which would be preferable, certainly, to the patient, if not to the drug company.

  17. Gan says:

    The phenomenon of a “reverse tolerance” is pretty talked-about in the drug community; I’m not sure how much scientific basis there is for it, but: This would be related to naltrexone though markedly different — it occurs a lot with marijuana, salvia and sometimes with caffeine, where initial dosing will have no effect, and it’s only after 2, 3, 4, 5 attempts at getting high on the new substance that it “clicks.” I think there’s some (justified) speculation that this effect, particularly in marijuana/salvia, is a product of first-time users who don’t know how to properly inhale. While that definitely contributes to the phenomenon, I’ve experienced/witnessed it happen with experienced smokers moving to a new smoked/vaporized substance. It also doesn’t explain caffeine, phenibut, or the racetams (and other orally-consumed nootropics) though it’s possible that this is due to these chemicals’ relatively subtle effects, which might require a bit of experience to detect.

    Anyone else have such an experience with this kind of reverse tolerance?

  18. Just some anonymous says:

    Off-topic – I’m one of those unfortunates who do not metabolize narcotic painkillers other than morphine. (And for some reason it is always really hard to convince the doctors that there is absolutely no point in prescribing or giving me these.) In a situation where I am in real need of a strong painkiller, and NSAIDs are off-limits for some reason, do I have any options other than Tylenol that I can ask for?

    • Garrett says:

      Can you provide a little bit more detail on what you mean by a few of your statements. Some of the terminology you are using is used in the medical field, but may be ambiguous in meaning or not quite used in a way that lines up with how you are using it.

      For example, narcotic. Legally, that’s a very large category of drugs including opiates (like morphine), marijuana and others. According to the NIH the medical meaning includes only opiates. Non-opiate (possibly narcotic) pain meds include ketamine.

      The other one is “metabolize”. That roughly means to be broken down by the body. This usually refers to breaking something down so that it is no longer effective and can be more easily eliminated by the body. However, there are prodrugs which are inactive in the body but the first pass of metabolism turns them into an active drug. Eg. Vyvanse. So stating that you can’t metabolize narcotics implies that they never break down and so a single dose would last potentially days. The exception being prodrugs (which I just discovered include a whole pile of drugs like codeine, oxycodone, hydrocodone, and tramadol which are processed by a single enzyme CYP2D6 – damn!).

      So, I’ll let others chime in with professional advice, but it looks like you’d be able to use morphine, Dilaudid, ketamine, and fentanyl (which is available in a patch).

      • Just some anonymous says:

        Sorry for using the terms incorrectly. I’m not a doctor.

        Codeine, oxycodone, hydrocodone, and possibly more in that group (I lost track of all that has been tried on me), have absolutely no effect on me. No pain relief, no mental changes, nothing whatsoever that I can notice. Morphine works, but some other drug I was getting through PCA (and that I believe was supposed to metabolize to morphine) did absolutely nothing.

        One doctor told me this problem is not as uncommon as people think, but nobody seems to be equipped to deal with it. In a situation that excludes NSAIDs, it seems to be the above-mentioned drugs, Tylenol, or nothing.

        I guess drug development is just not targeted at people with rare gene variations.

    • Adam says:

      Assuming the NSAID prohibition is because of ulcers, you can also try Celebrex.

  19. Anodos says:

    Is it possible that some people being prescribed powerful dugs never display a tolerance because they aren’t actually _using_ the drugs, but rather reselling them or sharing them with people? I feel like this may be a non-negligible segment of people being prescribed strong medication. I’m sure there are other pharmacological things at work, but could this hypothetical account for at least some of the results that you’re seeing?

    • jlow says:

      It’s rare to be prescribed powerful opioids without having something obvious causing real pain — just try to get oxycodone without something un-fakeable to show the doctor. It’s not unheard-of, with a certain sort of doctor, but presumably most doctors (and patients) are honest.

      • Anodos says:

        I was thinking more along the lines of Xanax, Adderall, etc, where the criteria for diagnosis and prescription are less universally measurable. I’m not accusing doctors of malfeasance or knowingly enabling this behavior, I am wondering if for psychiatric conditions that have imperfect or wholly subjective diagnostics there could be more abuse than Scott or most people in this discussion seem to consider.

        I should think this could create quite a bit of noise in surveys of patients’ tolerance buildup or responses, and potentially even account for some of the “sudden changes” that occur after a long time of no problems as patients begin actually using the meds as directed. When you have a market for nootropics that can make you a superhuman scholar or let you sleep near-instantly without going through an ordeal of diagnosis with a disorder, it seems the potential for a black market or grey “sharing market” would easily emerge for these meds, appearing in prescribers accounts as a lack of tolerance buildup. Having lived outside of high-trust communities for a while now, I believe it is naive to assume that most people/patients are honest brokers in situations like that.

  20. dangerduck says:

    Doesn’t it depend on whether the substance alters the brain/the way the mind now perceives the substance?

  21. vV_Vv says:

    Suppose that you have a computer running a program that you know has some bug which causes some undesirable behavior and you want to fix it.

    But you can’t modify the program. In fact, you can’t even understand it, it is written in a programming language unknown to you, and the CPU itself uses an unknown instruction set. The only things that you can do are macroscopic electronic interventions on the motherboard: change the frequency of the clock signals, the voltage of the power supply, the impedance of certain paths, and so on.

    After lots of trial and error experimentation, you notice that some interventions tend to cause the faulty behavior disappear, or at least become less frequent, but there is lots of variability between slightly different models of the same computer, or even between different units of the same model, or even in the same unit at different times. Likewise, your interventions tend to cause various largely unpredictable side effects, i.e. other kinds of faulty behavior which you may or may not consider acceptable tradeoffs, again with lots of variability.

    You may try to develop a theory about how the interventions affect behavior: high voltage causes failures of type X, low frequency causes failures of type Y, etc. but it gets all messy and complicated, with lots of non-linear, non-monotonic effects, weird interactions, and so on. The best you could hope for is something like “Could a neuroscientist understand a microprocessor?”, in practice your understanding would be much worse because your interventions and your ability to monitor are much coarser than those in that simulated experiment.

    Sounds like a pretty crazy way to fix a bug, doesn’t it? That’s pretty much what psychiatry is about, largely for the lack of a better option.

  22. baconbacon says:

    For some weird, anecdotal, stories about tolerance, my seasonal allergies.

    I had moderately bad to pretty bad seasonal allergies, first I would build a tolerance to every over the counter remedy I tried (Claritin, Allegra, whatever) where the first few usages felt like I had found a near perfect cure for my allergies, with a steady decline in their effectiveness to the point where they did nothing at all as far as I could tell (benedril the lone exception). I have tried some natural remedies as well (local raw honey/milk/nettle tea, the nettle tea I still use on my worst days which aren’t to bad).

    Then I spent 2 years working in bakeries on little sleep (midnight to 8 shift etc), where the flour in the air would often just hammer me into long sneezing fits, watery eyes and exhaustion. In the 3 years since quitting have been my mildest allergy seasons of my life (that I can remember, and by a lot). I sort of suspect that I overloaded my receptors and now it takes a really bad allergy day to set me off at all.

  23. Karl Lembke says:

    One idea I’d love to see people play with is the notion of inhibitory receptors.

    Consider a system where a molecule, maybe an endorphin, maybe something else, is secreted into the brain. Call it “E”.

    This molecule fits into certain receptors in the brain to cause some effect, such as decreasing pain or regulating brain function.

    A second receptor fits a different part of the molecule. When this receptor is filled, it tells the body to stop manufacturing that molecule. Production is inhibited.

    Now, suppose you give a patient a molecule (call it “M”) that’s similar in shape to the naturally occurring molecule. It almost fits the E receptors — not perfectly, but well enough to mimic its function. Maybe the poorer fit means the molecule shakes loose sooner than the E molecule does.
    Will this molecule also fit into the inhibitory receptor? Maybe not.
    If it doesn’t work the inhibitory receptor as well as the E molecule, there’s no signal saying “enough!” More of the E molecule is produced until the inhibitory receptors are triggered. You wind up flooding the E receptors well above the point where the “enough!” signals would kick in.

    Another possibility might be that the M molecule fits the inhibitory receptors a bit too well. When the E molecule will shake loose after a certain amount of time, the M molecule hangs on for longer. This might result in underproduction of the E molecule, meaning that whatever the E molecule is supposed to regulate goes unregulated, and a fresh dose of the M molecule is the only way to calm the situation down.

    If this is a mechanism accounting for physical addiction, maybe one approach would involve creating a molecule that fits the inhibitory receptors for E, but lets go much more quickly.

    Just a thought.

    • LPSP says:

      Seems like a good thought to me. Then again, if we have ways of studying how molecules affect certain pathways already, would examples like this not have been caught already?

  24. Q says:

    I did not read the whole thing, got impatient, but my quick answer is, that some metabolizing enzymes are inducible, while some are produced at plus minus constant level.

  25. baconbacon says:

    This seems relevant. In my teens to mid twenties I went through dozens (hundreds?) of depressed periods that lasted very short lengths of time. On the order of 3-24 hours for most of them with just a handful longer than that (none longer than 3 or 4 days). This was from the early 90s through the early 2000s (graduated HS in 1997), and when I looked depression up online I saw two things. One was that the description of what I felt matched clinical depression very closely, I remember feeling complete hopelessness, inability (unwillingness?) to move my limbs, suicidal thoughts (including some minor cutting at times), feelings of worthlessness. The other was that I clearly didn’t have clinical depression since it didn’t last nearly long enough, and I had basically no spiral or descent into depression (it was almost like turning a switch, maybe a good way to describe it is falling down a flight of stairs- clearly a progression, but a very fast and unstoppable one) in fact I couldn’t find anything online about it in that time period that seemed to match my experiences at all.

    I bring this up for 3 reasons.

    1. I am very open to the idea of individuals reacting to similar causes in wildly different ways.
    2. I never talked to a psychiatrist about this, so is this type of depression a common thing and I was a googletard in the 90s?
    3. I think I have built up a tolerance to my depression. I will still get individual symptoms, feelings or worthlessness (the most common), or the occasional heavy limbs where I feel like I have to crawl up the stairs to get to bed, or even thoughts of suicide (but since unaccompanied by the others they seem almost benign, it almost feels like an option I am not interested in). They last about the same length of time (several hours to a day or two), but never hit all together (or haven’t for years).

    • LPSP says:

      From what little experience I have of depression, the falling down a steep slope metaphor most aptly describes my feeling. I’d call it “Cliff-face Depression” if it needed its own term. I wonder if something does exist for it already?

  26. onyomi says:

    Not to turn everything political, but does anyone notice the similarity to government programs?

    “Hey, poor people need money. Let’s try giving them money.”

    Result five years later: some poor people doing better, some worse, some the same, as we’d expect if we hadn’t given the money (though if the distribution of outcomes is not, at least, somehow different, one wouldn’t be able to tell the difference between having done this and done nothing).

    • Ninmesara says:

      I don’t see the relationship between this and pharmacological therapy. Could you elaborate?

      • John Schilling says:

        I believe the intended analogy is that people may develop a tolerance to cash infusions just as they develop a tolerance to drugs. The sensitivity of the “I am spending too much and need to cut back on things that aren’t necessary” and “I need this expensive thing to be happy and fulfilled” receptors adjust to the mid-term average income level. The effect of giving someone an extra $500/month is thus transient happiness while they adapt and then they get evicted for not paying the rent anyhow – but there are more and fancier luxury goods in the pile next to them on the sidewalk.

        Naturally, when we investigate this in detail we will find that it is both true and false and weird in all the ways Scott has noted for pharmaceutical drugs, and we will have no useful guidance for future government interventions.

    • FullMeta_Rationalist says:


  27. Rm says:

    I wonder if there are any other drugs, prescribed for other reasons than pain issues, which can induce tolerance.

    • Ninmesara says:

      Organic nitrates prescribed for angina (chest pain from decreased oxygen supply to the heart) induce tolerance unless there is a drug free interval (usually 8-12 hours per day). Although nitrates are used for chest pain, they are completely different from normal painkillers, as they don’t work by modulating pain perception, so I guess they count.

  28. bob goodwin says:

    I take Ritalin, SSRIs, have had involuntary muscle movements for years after a surgery, take anxiety meds, and have experienced several other things you talk about. I take a LOT of Ritalin, and it stabilizes, and I have never had to up the dose. Apparently my Dopamine is quite low, and yet my body jerked. I also have low latent inhibition (that ganglia thing), which can make you twitch and be psychotic. I tried stopping the Ritalin and the twitching went down 10% and I could not concentrate. So as you discuss beautifully how strange this world is, from the inside it feels like a multivariate non linear response system, with saturation, overshoot and hysteresis. I may sound like a mess, but I am very high functioning.

    That’s my 2c.

  29. LPSP says:

    I’d definitely put a smidge more money on the “genetic differences in tolerance” theory. It makes sense, after all, that some environmentals and societal roles reward adaptive hardiness, while others reward consistent sensitive clarity. I wouldn’t be surprised if individuals who quickly develop a tolerance for stimulus happen to be tough, belligerent, defensive characters, and the opposite the opposite.

    As for “digging ditches and filling them in”, I’d say it’s more like run both hot and cold water into the bath at once to achieve a temperature balance. Or having both an oven and fridge running at once, or pulling on both ends of a rope. Keep the right tension there; don’t let the system fall into slack disarray.

  30. onyomi says:

    Maybe instead of spending so much time looking for substances that make us feel better, we should look for substances that make us feel so bad, they somehow permanently destroy our feeling bad sensors. (I actually suspect this may be how some things work, which would explain why some drugs, like SSRIs, take a month to work).

    • Nornagest says:

      I have a half-assed theory that torturous initiation rituals are so common across societies partly because they act to reset the victim’s set point for misery.

      • LPSP says:

        I really wouldn’t call that half-assed, it’s the basis of the armed forces, animal rearing, and arguably parenting and schooling.

        • onyomi says:

          But we don’t have any drugs or substances which do it?

          • LPSP says:

            Not that I’m aware of? The conversation shifted towards related torture experiences and whether they exist or not.

            Maybe bitter, sour, scorchingly-spicy or other stringent and acerbic foodstuffs qualify? I know I had trouble handling a beer at 13, but could down pint after pint at 20. Similarly, eating food with a thai household trained me to find the old Indian takeaways I found difficult permanently easy.

          • Lumifer says:


          • Nornagest says:

            Capsaicin is used as an analgesic, and the mechanism of action is supposed to be something like this — it binds to a family of heat receptors and the signals coming from that crowd out the signals coming from whatever pain you’re trying to reduce, or something like that. But I assume it’s not quite that simple, or the cure would be worse than the disease.

          • Deiseach says:

            Traditional remedy of using stinging nettle for arthritis? Modern methods are taking extracts in the form of teas or capsules, but the hardier folk of yore used to apply the nettle to the affected part – the idea seems to have been the pain of the nettle stings drove out the pain of the arthritis.

            There was also the custom of consuming the new growth of nettles in spring, when the plants were young and hadn’t developed the stings yet, as a tonic and blood purifier, in teas and soups (never tried it myself).

          • Lumifer says:

            @ Deiseach

            the pain of the nettle stings drove out the pain of the arthritis

            Pretty sure it just local irritation -> increased flow of blood to this particular area. Same idea as mustard plaster or tiger balm — pain is not actually required.

      • Florian says:

        I had a similar thought recently. I wonder if I could learn to tolerate pain by enduring some form of torture.

        But I see a problem here. Torture and pain can become addictive when they can be switched on and off and controlled by the torturee or torturer. The whole BDSM thing is based on dopamine release during the “play sessions”.

        It should be something really unpleasant which you can’t turn off in an instant to enjoy the dopamine rush, but something which you would have to endure. Withdrawal symptons or pain in a pill that lasts some time.

        • Rebecca Friedman says:

          Try picking blackberries without bothering with gloves or long sleeves, in an area partially overgrown with roses.

          … I jest, but only somewhat. IME, living one’s life without a severe regard for pain (serious negative consequences yes, pain no) does build pain tolerance. Even from something as minor as thorny berry bushes.

          … it’s also very unpleasant while you’re doing it and I’m not sure I would seriously recommend it, but…

    • Adam says:

      This is 90% of all military training.

    • FullMeta_Rationalist says:

      When I was younger, I wondered what the opposite of addiction was (i.e. bad short-term; good long-term). Then I realized it’s called exercise.

  31. GregS says:

    This was a great post. It was interesting to me because I’ve spent the last week and a half experiencing caffeine withdrawals. Headaches, general feeling of sleepiness, muscle aches and spasms. Surprisingly no actual cravings, though. I’m thinking I’ll probably drink coffee again, but I don’t feel any urge whatsoever to get a cup. I spend some time thinking about how I might react to some caffeine and how it might relieve my symptoms, but it’s purely intellectual. I don’t feel like I’m trying to justify a craving, because the impulse really isn’t there. I’m curious how I’ll respond to coffee when I try it again. I have no sense of how much tolerance I’ve built up, but given my withdrawal symptoms I’m sure it’s significant.

    • Octapode says:

      From personal experience, due to quitting caffeine when I go to uni and restarting when I go home: tolerance does reset, not sure on the exact timescale. However, it very quickly returns once you start taking caffeine again, and you’ll be right back where you were before quitting in maybe just a few days. This seems pretty much endlessly repeatable, and in the off cycle there’s no lingering impact. Your withdawals should be almost over if my experience carrys, but they are the suck while they go. Good luck to you.

      • GregS says:

        Thanks. I’m mostly out of the woods now as far as withdrawal goes. I’ve read several things that say drinking coffee has no proven health hazards and probably actually has some benefits (staving off Alzheimer’s for example). (The books Buzzed and Karch’s Pathology of Drug Abuse both have sections on caffeine.) I’ve also read that caffeine disrupts your sleep cycle, which I think was becoming a problem for me. I felt like I wasn’t getting the deep, restorative sleep I needed. I’m going to see if completely eliminating caffeine makes a difference. I’ll probably start drinking it once a week or something like that. I was drinking a mix of half-decaf, half-caffeinated throughout the day, but it was kind of pointless because I had built up a tolerance. I could drink a cup over my lunch break while reading a book and still nod off. So I probably won’t go back to regular use.

    • Florian says:

      I’ve just been through a two day apex of an ongoing caffeine withdrawal period myself. It totally took me by surprise. The culprit were three cups of black tea on three – not even consecutive – evenings this week plus only 4 hour sleep for two days and maybe one cup of coffee in the afternoon on the first day the withdrawal symptons first appeared (I was still at work and had to get rid of the headache immediately, the coffee didn’t help much). Yesterday and on this weekend I have my days off, so I have time to recover. Not really what I had planned.

      I have quit caffeine several times. Most recently was several weeks ago during holiday. I have to do it during a vacation because I need a dark room and several days of quiet to get through the headaches. I could have just called in sick, but I’m not that kind of person. Anyway now I sleep well, at least I think so, but I get tired easily when I have a day off which would suggest otherwise. Also when I “accumulate” lack of sleep, like at the beginning of this week, I get tension headaches quickly. And then I crave sleep, like someone would crave painkillers. Now after reading Scott’s blog post I got the hunch my adenosine receptors might have become oversensitive because of years of caffeine abuse and weaning, abuse of weaning. My new routine without coffee or tea just barely keeps them in check. Too much adenosine is just too much.

      I imagined a little bit of caffeine in the form of a mild cup of tea after work might be ok to keep me in an active mood for the evening, but I guess I will need months before I can enjoy a cup of tea again. And it’s probably the best to get more sleep the night before if I plan to do something after work the next day.

      Another hypothesis I have when it comes to kicking the caffeine habit is that – considering sleep helps miracles against the headaches – sleep too (same as caffeine) during the withdrawal only delays the detox. I have to desensitize my brain to adenosine for the receptors to fully recover again and I fear not only do I have to stay away from caffeine completely but also refrain from too much sleep and especially resist the urge to do an afternoon nap even if it makes me feel miserable. One thing I’m pretty sure is that during a caffein withdrawal I can’t cheat my way out of the horrible headaches, I have to endure them.

      I guess a “normal” person who only sleeps 4 hours a night the whole week would just experience the normal symptons of not getting enough sleep, but if I do such a thing I get symptons analogous to caffeine withdrawal. So it’s no naps for a few weeks, no sleep longer than 9 hours. It’s just a hunch I will test out, it’s placebo prone and these recent headaches may as well have been caused by actual strained neck muscles or stress. Or I may be suffering from chronic tension headaches and wrongfully attribute it to caffeine and sleep deprecation. Although I kind of believe that a lot of patients with chronic tension headaches actually have a problem with caffeine withdrawal.

      Even though I did drink tea the last week, getting headaches for not sleeping enough has happened to me before, only after the last caffeine detox where I used sleep extensively to sooth the headaches. I fear it might be a thing, and it’s worrying me. Sleep has become my number one remedy for headaches and I was happy with that, but now I get the feeling it might not have been such a good thing after all and my adenosine receptors aren’t back to normal at all.

      • Rebecca Friedman says:

        For whatever it is worth, I am a person who under normal conditions doesn’t get headaches, ever. The main non-normal condition that triggers them is sleep deprivation. I don’t do caffeine in general, so I doubt that’s a factor in my case. Don’t know if that’s helpful, but figured it was similar enough to maybe be.

  32. Yes, I'm judging you. says:

    I have been prescribed Xanax, and have taken it because I needed it. The last time I needed it was over 5 years ago.

    When my PCP wrote the prescription for me, it was only after a Very Serious conversation about benzos. Apparently one of the things he does is help people get off benzos safely, and he expressed frustration in other doctors who hand them out too casually.

    Some of the things he emphasized heavily:
    * Don’t take one unless I have literally run out of cope, and I can actually feel the panic attack coming on. The very act of taking the pill will help me calm down, because much of the stress of a recurring panic attack is the feeling of being out of control, especially where other people may see, and the simple fact knowing that the panic attack will get squelched by the benzo will make the panic attack less severe, and may even prevent it
    * Absolutely do not drink any alcohol whatsoever for 3 days after taking a Xanax, not even half a glass of wine. If possible, don’t take a Xanax sooner than 12 hours after drinking any alcohol.
    * Some of the final stage metabolites of Xanax, which show up a day or two later, themselves can cause anxiety. Ain’t that a funny joke, right? So, if I feel a panic attack coming on 2 or 3 days after taking a Xanax, avoid taking another one, and instead try to retreat to a hiding place, and ride it out while telling myself that.

    I took them when I needed them, and then after over a year of not needing one, I threw ones I had not taken into the trash.

    • Anxious Arthur says:

      Is Xanax really that dangerous? No alcohol for three days seems unrealistic. I know benzos and alcohol are a dangerous combination, but the biological half-life of Xanax is only 11 hours, so it seems like one day should be more than enough unless you’re taking massive quantities of Xanax. (I don’t drink, so it doesn’t matter to me anyway.)

      • Deiseach says:

        Possibly the doctor was working on the assumption that, since some people will go “I need liquid to help me swallow this tablet – ah yeah, that glass of whiskey will do fine”, by being Very Serious about “3 days no alcohol” it might ensure that people waited a day before drinking before/after taking the Xanax?

      • Yes, i am judging you says:

        To my sorrow, I know untreated alcoholics and other people who use drugs recreationally to the point of damaging their health and their social networks.

        It is a Thing that addicts will take a benzo and then get drunk, because the alcoholic buzz lasts longer. Much longer. Much much longer. And when you are a nearly broke addict, something that lets you go on a 2 day bender with just a cup or two of cheap vodka is seen as frugality and a good way to economize. A theory is that while your liver is working on the benzo metabolites, it can’t clear the alcohol metabolites. I don’t know how true this may actually be, but I have seen people stay drunk for two days using this technique.

        It’s also very much a thing that someone who actually really needs a bezo for anxiety may also be trying to self medicate with alcohol, and this must be firmly discouraged. And it’s also a thing that using enough alcohol to medicate anxiety can have effects on your behavior and social life that will correctly cause yet more anxiety once you are sober again.

        Me, myself, in that time of my life, I stopped drinking, completely.

  33. switchnode says:

    Forgive me; I am not up on psychopharmacology. But the paragraph on antipsychotics and dyskinesia (beginning “Sometimes tolerance gets weird”) is extremely confusing. If the effect of psychotics is to block dopamine receptors, wouldn’t increased production of dopamine be a natural negative-feedback response that could explain dopaminergic effects? From that perspective the tolerance would be perfectly straightforward, not the weird reversal you describe it as.

    (It wouldn’t explain the difference between the psychosis-related pathways and the movement-related ones, but that could be a separate issue either way—slightly different receptor types blocked to different extents, or similar.)

    Is there (as I assume) some evidence this isn’t the case that is simply elided in the post? What are the details?

    • Scott Alexander says:

      Yes, that part makes perfect sense. What doesn’t make perfect sense is:

      1. Why instead of going back to the normal level of dopaminergic transmission, you end up with *too much* dopaminergic transmission.
      2. Why this is permanent, and lasts even after you discontinue the antipsychotic.

      • FullMeta_Rationalist says:

        I’m no doctor either. But isn’t that how vaccines work?

        random hypothesis:

        Immune System: “A pathogen ate half our dopamine! Let’s immunize the brain by permanently adding dopamine receptors.”

  34. It is extremely difficult to assess the effects of an addictive drug objectively. It is well know that practically anyone who tolerates and takes a stimulant believes that they are functioning better on it because of a number of reinforcing effects. The effects on declarative memory and executive function are much more modest than most people realize. In that vacuum – it is very common to increase the doses of medication and even add additional doses of “rescue” medications later in the day. There appears to be very little objective basis for high doses of stimulants (beyond the FDA recommended max doses) or rescue medications.

    To highlight a similar situation, when I was completing my residency we were dealing with the tail end of a significant population of people who were treated with stimulants for obesity and/or neurasthenia. The people being seen for weight loss were all at least 100% over ideal body weight. My standard question was to ask people how much weight they had lost on high dose stimulants for 10-20 years. That amount was usually none and in many cases additional weight had been gained. My follow up question was why they wanted to stay on a medication that had failed the primary indication. They could not tell me why.

    My speculation is that even apart from the obvious cravings and preoccupation that develop with addiction, the conscious state is affected in more subtle ways by addictive drugs. If there is a drug that alters a feeling state or even causes subtle changes in an area that a person may feel deficient it may becomes highly reinforcing – even if that happens for a brief period of time.

    That makes the prescribing of addictive drugs very frustrating and in many cases an impossible task for clinicians. There are no objective measurements and a 10-point rating scale at some point turns into a joke.

  35. Seb says:

    Funny you should post that – I previously tried to speak to you on Twitter and that was to ask about PAWS. Someone very close to me has suffered from an opiate addiction in Iran for *decades*, and has been off the drug for a year now. THe withdrawal was hard enough, but treating PAWS seems almost impossible for that level of use. For the person concerned the antidepressant have so far been pretty useless. What strikes me is that so many of these rehab or post-rehab centres where I am (Europe) do not appearto have ever heard of PAWS, which is slightly concerning. So yeah, perhaps time will help, but hoping more research goes into this – very sad thing to see.

    • Scott Alexander says:

      I’m sorry I apparently didn’t see your Twitter comment.

      I have tried low dose naltrexone once for PAWS, but it caused so much sleep disturbance that the patient didn’t stick with it. It might be worth seeing if your friend has tried this.

      I have a crackpot theory, so far totally untested, that tianeptine might help with PAWS related depression. It seems to have some kind of novel opiate-related mechanism of action. If your friend is also in Europe, he might want to try that too.

      • Gan says:

        Tianeptine almost definitely has opioid action; in my experience, it starts resembling an opiate high pretty closely at around 100mg. I used it for withdrawals from U-47700 and ODSMT (mostly acute, but some during the 2-4weeks after quitting, during the in-between zone). It helped pretty significantly. If you can’t manage to get a prescription for suboxone, which I understand is pretty tough, loperamide is one of your only available withdrawal med besides T. that does any good (kratom works for some people but the rate of addiction-swapping is notoriously high). I don’t know how common tianeptine usage is for withdrawals within opiate communities, but I know the RC communities have thus far embraced it to some degree (the opiate and RC-opiate communities are pretty divided and don’t get along). My impression is the chemical will unfortunately go the way of U-4 and now kratom, with states (U.S.) and European nations slowly legislating bans. That process will probably happen slower than did for U-4 since the overdose risk is so much lower.

        I’ve also heard success stories about tianeptine, at doses between 12.5 and 40mg, working as a short-term antidepressant (for something like SAD, for example, used only 1-2 months a year). Obviously all the standard disclaimers about non-prescribed, novel/less-researched “research” chemicals apply (though tianeptine has a pretty substantial history of medical use outside the US). I want to stress that I’m not looking to encourage anyone on this forum to recklessly try these chemicals. Most people who are deep enough in drug communities to know about RC opioids own milligram scales, have read up meticulously, use test kits, and have years or decades of experience under their belts to safely work up from threshold doses or immediately identify signs of overdose. But, for science (and what it’s worth), spilling my accumulated knowledge.

        • jlow says:

          Thanks for this, Gan. I used to be obsessively interested in RC opioids, but I gave up due to essentially no success at all — U-4 was the only one I was aware of, near the end of my “career”, and by the time I was able to source it, it was banned. (This is not counting kratom, which is surprisingly opioid-like but wasn’t quite close enough for me.)

          Ah, all the wasted effort on loperamide… the only good thing that came from that was finding that it takes away about 90% of withdrawal effects. You’ll never get any euphoria or worthwhile “loperamoid” out of it, though, was my conclusion.

      • Seb says:

        No worries! I’ll see about the Nalextrone – his sleep is already pretty disturbed, even a year post-withdrawal, so I guess it can’t get worse… He did mention trying naxolone once but that apparently was an exteremely painful experience (not sure why, as most other people using it to decrease withdrawal symptoms seemed fine). Will have a look at tianeptine too, cheers.

    • jlow says:

      Rehab centers seem to be incredibly ignorant in general.

      For PAWS, my friend used cannabis. Maybe not an option in Iran. Suboxone is a lifesaver if available, and if one has no philosophical objection to taking a med for the foreseeable/near future.

      (I never quite understood the objection myself, but some want to be “totally clean from ‘chemicals'” — with exceptions for all the various socially acceptable chemicals, like caffeine, and “natural”-seeming ones, like food…)

  36. onyomi says:

    One of the reasons that I now avoid all drugs as much as possible is that not only do I often have atypical reactions which doctors never believe in (“this drug made you feel like you were losing your mind? That isn’t listed as one of the side effects. Maybe you should try a higher dose?”), I sometimes have strongly divergent reactions to the same exact drug, especially if a significant time has elapsed (though generally I am still much more receptive to trying a drug I’ve tried before without a problem). “Five years ago this drug lulled you into a peaceful sleep and now it gives you a panic attack? That shouldn’t happen… maybe try a higher dose?”

    So, yeah. Now I just try to avoid drugs (and doctors) as much as possible.

    • jlow says:

      I sympathize, because my mother has the same problem. I wonder if it’s possible that some people have wildly atypical biochemistry or something, because that’s now two people I know of who react weirdly to *everything* (instead of weird reactions being spread out with specific substances and people).

      However, to defend the medical profession, you’ll find that a lot of people have baseless ideas about “special” reactions to drugs — the girl who doesn’t get sleepy on diphenhydramine but does on Benadryl, the guy who gets an amazing side effect from every drug you can name, the woman who says the pill makes her twitch a few seconds after ingesting — so you get skeptical pretty quickly when apparently-impossible objections come up.

    • Anonymous Soup says:

      This is more of a doctor problem than a drug problem though. Not that finding one is a trivial option, but every doctor I’ve had improvements with has embraced the concept that the patient is an expert in the patient’s symptoms.

  37. Raza says:

    I like your thinking, particularly about us needing more tricks like LDN!

    To get to the question, I think physiological drug tolerance is more complicated than all receptors of a given kind, such as 5HT2A or mu, desensitizing simultaneously and evenly across the brain. Metabolic receptors such as the serotonin, dopamine and opiate families have perhaps a dozen proteins in their signalling cascades, and often negative feedback loops are in effect at different levels, capable of (over)compensating for the previous step’s control mechanism’s overcompensation. A D2 receptor in a frontal cortex neuron doesn’t necessarily have the same intracellular signalling cascade exerting the effects of its activation as a D2 receptor in the basal ganglia, leaving room for different negative feedback patterns to arise from the same patterns of extracellular drug concentration. Worse, even neurons expressing the same receptor type supported by what is qualitatively the same intracellular signalling cascade can (and often will) be ‘tuned’ to respond differently on account of quantitative differences in the expression of any of the protein(subunits) involved, and such differences seem to exist both between different neuron populations with the same person and between different people. And regularly, downstream from where a drug hits its receptor, different signalling cascades split off in different directions, each having its own role in the drug’s subjective effect, and each subject to its own negative feedback mechanisms. There’s more: drugs may not be evenly distributed across the brain; different drugs hitting the same receptor may target different parts of it and trigger different negative feedback mechanisms; and behavioral & cognitive tolerance may build selectively and/or reversibly for effects that involve changed communication between neurons downstream from the original target, such as euphoria and LSD hallucinations, whereby the brain learning to predict the effects may be enough to silence them.

    This means that seemingly paradoxical reactions really aren’t that unexpected, and you’d really need a whole quantitative systems biology model with all kinds of information we don’t have to fully predict what a drug’s effects are going to be after nine months of use in a given individual.

  38. mayleaf says:

    FWIW, everyone I’ve talked to who’s taken Adderall regularly for >6 months has noticed tolerance. (And everyone I know who’s been on prescription ADHD meds for >1 year has had their dosage upped at least once, often several times, by their psychiatrist.)

    I’ve also read the studies that claim that “tolerance doesn’t happen” — then again, all of these were studies that lasted 4-8 weeks, and that’s a shorter timescale then I’ve personally seen for developing tolerance to Adderall. Scott, did you find any long-term (>6 month) studies that found no tolerance for Adderall or other stimulants?

    My ex-boyfriend was diagnosed with ADHD about 10 years ago, a started on a low dose of stimulants, and years later ended up on the highest possible dose of Vyvanse. At that point, he no longer got productivity benefits from Vyvanse, but he needed to take the Vyvanse daily or he’d feel sleepy all the time.

    I’ve personally had similar experiences, and have found that if I stop taking stimulants for weeks or months, I can start using them again and they’ll be as effective as before.

    • Protagoras says:

      I took dextroamphetamine for a few years and didn’t really see any signs of tolerance developing.

    • HeelBearCub says:

      I take Adderal XR and I am now at about 7.5 mg per day(I take about 1/2 of a 15 mg capsule each day).

      I started at 5 mg. Worked my way up to 20, and then back down to 7.5 mg. I worked down from 20 because I had dry mouth and it was causing me issues.

      Basically, if I don’t take the Adderal I get very, very, very cranky. Being very cranky is why I started down the path that led to the Adult ADHD diagnosis, so this is not surprising. Otherwise, I only noticed that I unintentionally increased my caffeine intake as I ramped down the dose.

      I never got super-amped on the Adderal, although there was some of that early on. Mostly it just makes me feel “normal” instead of “broken”.

    • Mammon says:

      I took adderall and dexedrine for respectively two and four years, I’ve never noticed a tolerance. If anything, my dose has gone down.

  39. The problem with receptor effects in psychiatry and medicine is that unless they are studied in very controlled situations – they are strictly qualitative and the actual receptor effect is uncertain. For example consider a hypothetical residential treatment program for opioid use disorders. The clinicians on staff know that if anyone seeks admission taking high dose methadone from a maintenance program that the withdrawal may be protracted to the point that the entire course of 30 days of treatment is dedicated to it. They may establish a maximum number of mg of methadone that a patient can come in on based on their referral base and experience detoxifying people from opioids.

    With methadone it is well established that a small but significant number of people are slow metabolizers, but this is rarely determined on a clinical basis. Methadone is typically titrated based solely on clinical criteria. A significant number amount of tolerance to methadone and several other addictive drugs is based on metabolic factors. I have not seen a study looking at the issue of slow metabolism and the protracted withdrawal state from methadone.

    The Ki for methadone at the mu receptor is significant and is easily in the ballpark for other high potency opioids:

    On the other hand some opioid withdrawal symptoms can be covered by tramadol that has a mu receptor affinity that is a fraction of methadone.

    Receptor based mechanisms such as these detailed cartoon drawings from KEGG – hint at the complexity based on receptor, post receptor,and cell signalling mechanisms:

    Whether or not the proposed mechanisms from KEGG is accurate or not with regard to opioid acute and chronic withdrawal – it highlights the total proteins involved that probably account for the diverse response to opioids from the outset. Not everyone is wired for the euphorigenic, hypomanic response to opioids that seem to predispose people to addiction. One very good study of neuropathic pain treated with levorphanol in the NEJM where the dose was titrated by research subjects showed that up to 27% of the patients became irritable and withdrew and this only happened in the high dose group. To me that suggests that different configurations in the relevant networks will determine the degree of withdrawal and associated dysphoria.

    A couple of other brief points – I think that there is no evidence that a supersensitivity psychosis state exists. There are undoubtedly a number of people who are sensitive to antipsychotics and highly susceptible to severe tardive syndromes. They must be recognized immediately and antipsychotic treatment must be stopped or clozapine can be tried in low doses. My best estimate is that these cases were all people who were sensitive to and unresponsive to antipsychotics and they were titrated to higher doses hoping things would improve.

    The issue of loss of antidepressant effect almost always has other explanations. It is confused by the low AD response rate at baseline and many, many people are treated with antidepressants who do not have depression. The commonest example is the chronically depressed person due to a lifetime situation (work, relationship, etc) that is not changing. The variance in AD response (that I would not expect them to respond to anyway) correlates with all of the psychosocial factors rather than loss of efficacy. It is a question of classification and the old neurotic-reactive depression versus endogenous depression. I think if you look at severe spontaneous depressives with severe depression – who remit with a medication – they tend to maintain that remission barring a clear complicating factor. They also have less of a placebo response. On the other hand there are many who are partially responsive or non-responsive to antidepressant effects and I don’t think there are clear ways to define them as resistant or tolerant. Typical pharmacological studies look a cut offs on rating scales as meaningful. I guess I don’t.

    Tolerance and withdrawal are not unitary phenomenon. I would not expect to see the same mechanism any more than there are identical mechanisms on the dopaminergic-reward end. Considering them to be unitary mechanisms allow for a number of misconceptions such as the classification of antidepressants as addictive drugs based on withdrawal phenomena.

  40. Lumifer says:

    I have a (little) pet theory that a lot of these issues follow from statistical illiteracy and in particular from not understanding — sometimes at the gut level and sometimes at any level — the difference between point estimates (especially averages) and full distributions.

    Say you run a study and you find out that intervention X improves some metric Y on the average by 20%. It’s a good study, the value is statistically significant, etc. Clearly it is a good intervention that works, right? That 20% number is what most people will take as the entire result of that study and they will expect 20% improvement from the intervention X. But this is a very incomplete view! You need know the width of the distribution of outcomes for a reasonable guess at what you should expect.

    Say the distribution of outcomes is bell-shaped and the standard deviation is 40% (the mean is 20%). What does that mean? To start with, this means that in about 30% of the cases the intervention will make things worse (for a normal distribution with mean 0.2 and sdev 0.4 the probability of getting a negative value is 0.3085). And sometimes it will make things a lot better: in about 22% of the cases the improvement will be more than 50%.

    So that 20% number is somewhat misleading — yes, it’s an average, but you should expect to see both negative values and large positive values on a very regular basis. And yet, most people will just see 20% and go “OK, so this intervention will produce a 20% improvement in almost all cases. Science says so!”.

    • Adam says:

      So much yes. Underspecified distributions seem to me to be a huge part of how people misunderstand intervention treatments of any sort. This doesn’t just apply to medicine but even laws, policing techniques, forms of larger government action, whether or not particular war tactics work.

  41. Mahan says:

    Check out these papers on the adaptive uses of dependence.

    McDonald, R. V., & Siegel, S. (2004) The potential role of drug-onset cues in drug dependence and withdrawal. Experimental and Clinical Psychopharmacology, 12, 23-26.

    Siegel, S. (2005). Drug tolerance, drug addiction, and drug anticipation. Current Directions in Psychological Science, 14, 296-300.

  42. Alex Zavoluk says:

    Initial thought: for most people, medicine restores you to “normal” functionality. You won’t build up a tolerance to normal amounts of Adderall because that’s what your body “expects” (in more specific terms, has mechanisms to handle it that don’t involve tolerance, because losing focus as you age would be something your body might have evolved to combat). You build up a tolerance if you use too much, or something not in your body naturally (like heroin) because your body doesn’t have a similar mechanism to handle it.

    Of course, exceptions can always exist.

    Is that plausible?

  43. Tyrant Overlord Killidia says:

    I don’t know how common this is, but for some reason I really don’t enjoy the feeling of e.g., Percocet or morphine the few times I’ve had them in hospitals.

    They didn’t really make the pain go away, and they made me feel all weird and loopy. It’s like “Not only does recovering from this surgery suck, but now I’m on this dumb medication that makes me feel loopy and I’m still in pain.” The only real benefit was that I slept a lot, which meant I wasn’t conscious in order to feel pain.

  44. Erebus says:

    -A drug that’s supposed to have effect X, but after a while it has no effect (heroin)
    —This drug could be a CAR or PXR agonist [1], could target a GPCR that’s easily desensitized [2], could target a receptor with a low reserve at one or more active sites [3], could be sensitive to transporter (MDR or P-gp) mediated efflux [4]…

    -A drug that’s supposed to have effect X, and after a while it still has effect X (Adderall)
    —Drugs that are none of the above are probably alright. Nuclear receptor agonists, as a class, seem to be generally alright — I’ve never heard of tolerance developing to a steroid hormone or a PPAR agonist.

    -A drug that’s supposed to have effect X, but after a while it overshoots and has effect anti-X (Antipsychotics? Heroin? Naltrexone?)
    —Nasal sprays that hit the alpha-adrenergic receptor are the best example of this. The pharmacology underlying such effects appears to be very complicated. But here’s something interesting: Those nasal sprays, every antipsychotic, heroin, and naltrexone all target GPCRs. “Rebound effects” might be unique to drugs which bind to GPCRs, as a result of the inactivation/internalization/degradation of those receptors.

    As for tachyphylaxis, I’d bet that this is almost always due to non-compliance, drug degradation due to improper storage or handling, reduced oral drug absorption due to dietary or metabolic factors, or the development of straightforward tolerance due to one of the reasons mentioned above.

    (1. Some drugs, but not others, bind to and activate “xenobiotic” receptors such as the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). Following activation, these receptors turbo-charge CYP450 drug metabolizing enzymes. These enzymes, in turn, chew-up drugs and endogenous substances at an accelerated rate. This helps to account for drug tolerance in CAR and PXR agonists — most famously in the case of phenobarbital and the barbituates.

    2. The opioid receptors, adrenergic receptors, serotonin receptors, dopamine receptors, cannabinoid receptors, and many others, are all GPCRs. Broadly speaking, prolonged stimulation of GPCRs leads to their phosphorylation. Proteins called β-arrestins subsequently bind to these phosphorylated receptors, prevent further interaction between the drug and the receptor, and induce receptor internalization — where most, but not all, of of the receptor’s functions are blocked.
    (GABA receptors, although they are GPCRs, do not appear to interact with β-arrestins, and do not appear to exhibit reduced protein or mRNA expression following long-term dosing. Benzodiazepine tolerance is a very complex phenomenon.)

    3. The receptor reserve is a well-known pharmacodynamic phenomenon. In short: Different tissue types express different receptors, and at different concentrations. In some tissue types, certain receptors are seen at unusually high concentrations, and binding to a mere fraction of them can suffice to produce the greatest possible pharmacological effect. In this type of case, the relationship between drug effect and receptor occupancy is non-linear. (Low receptor occupancy / strong pharmacological effect.) Given the fact that GPCR stimulation leads to receptor desensitization, it should be easy enough to see why different receptor concentrations in different tissue types can lead to tolerance developing to certain drug effects, but not others.

    As far as I am aware, this is why tolerance to morphine quickly develops in the CNS, develops more slowly in the upper gastrointestinal tract, and does not develop at all in the colon. (β-arrestin expression may also have something to do with this.)

    4. P-glycoprotein (P-Gp) and multidrug resistance–associated protein (MDR1) are transporter proteins that can lower intracellular concentrations of drugs; like bouncers ejecting folks from a busy bar, they eject drugs from the cell and prevent them from reaching their active sites. They generally underlie the phenomenon of chemotherapy resistance, but are, as far as I am aware, less of a factor where recreational drugs are concerned.)

    …Speaking of “a tolerance-free version of heroin”, JNJ-20788560 is a delta opioid agonist that is said to be tolerance-free. No respiratory depression, either. Whether or not it has recreational potential is anybody’s guess.

    • Garrett says:

      and does not develop at all in the colon

      Does this mean that ultimately, heroin users will only get the side-effect of constipation?

    • Josh says:

      Generally, the euphoric recreational effects are thought to come from the mu-opiod receptors.

  45. Sebastian H says:

    This discussion reveals why it is so sad that we aren’t researching ibogaine in a more comprehensive way. It seems to act as a hard reset of one or more of the systems described here. It would be nice to know which one or ones.

  46. Ankle says:

    “And a tolerance-free version of heroin would be pretty interesting too – from a purely pharmacological perspective, of course.”

    Who cares, it would still be banned.

  47. Pax_Empyrean says:

    There is a poorly-studied but anecdotally very helpful treatment for PAWS: low-dose naltrexone. Naively, this sounds like the stupidest possible thing to try. It’s an opiate antagonist, meaning that you’re taking somebody who is undersensitive to opiates and blocking the tiny number of functioning opiate receptors they already have. It should be the only thing capable of making this already bad condition worse. Yet people swear by it. The theory is supposed to be the tolerance reaction again. Your body reacts to this opiate-blocking agent by releasing more opiates. So we’re treating a condition in which drugs that increase opiates cause you to have fewer opiates, by giving you a drug that decreases opiates which will cause you to have more opiates. How annoying is that?

    Oh, have you never heard of tricking somebody’s brain chemistry into doing what you want with a little reverse psychiatry?

  48. Octapode says:

    A theory I have seen re: amphetamine tolerance is that there are two different kinds: short and long term. Short term is caused by dopamine depletion and will reset after a few days to a week, which I can confirm anecdotally. I would also extend this to say that this form of tolerance is strongly dose-dependant. Long-term tolerance, on the other hand, is speculated to be caused by damage to the relevant cells and receptors by excessive dopamine oxidation products getting reabsorbed and essentially burning out the areas amphetamine acts on. I do not have first-hand experience of this, fortunately, but I have seen a lot of accounts saying that this long-term tolerance is essentially permanent.

    This wouldn’t fully explain why medical use is less likely to produce tolerance than recreational, but given that medical doses are usually a lot lower than recreational, it could explain part of it.

  49. jld says:

    Well… if you want more weird facts about addictions (of any kind) you should look into Ibogaine.

  50. Oleg S. says:

    Somewhere out there there should be a kinase that senses accumulation of too much desensitized receptors and launches a signaling cascade that results in expression of a transcription factor which among other things stimulates production of a miRNA that causes permanent shutdown of production of a whole family of receptors. Or something.

  51. WellAnonymous says:

    (Commenting anonymously for privacy, semi-regular poster here).

    The first week I was on Wellbutrin, it felt like “OMFG, this is amazing.” There was a mild euphoria that let me go about my day just feeling absolutely swell. That diminished each day and after a couple of weeks, it was gone. I had built tolerance to the euphoric effect.

    I can see how recreational users would complain about building tolerance. It still works as an anti-depressant and with many fewer side-effects than the many SSRIs I tried before. It’s more about smoothing the lows than about giving me any highs.

  52. I am the Tarpitz says:

    LSD users report very strong tolerance lasting about three days after a dose, to the point where a second dose the day after will do almost nothing. Rat experiments have shown this is definitely because of receptor downregulation and not just enzyme induction. Okay. But LSD is a pretty strong drug. If receptors are so down-regulated that you are essentially on negative one tabs of LSD, how are you remotely normal while the tolerance is in effect? Are people during their periods of LSD tolerance less crazy and creative than normal?

    My experience of using LSD (only twice, some years ago, some months apart) was that I was very much not normal for around a week afterwards. The hallucinations and unusual thinking patterns lasted about 18-24 hours (though with diminishing intensity beyond perhaps the 4-6 hour mark, at a guess). After that… numb, muddled, non-specifically anxious, cotton-woolly. As I say, for about a week, though again with diminishing intensity as time went by. Assorted friends and acquaintances reported similar experiences. At no point did I try taking acid during this period, but I suppose it’s entirely possible nothing would have happened if I had.

    • Orphan Wilde says:

      I would get what I describe as a hangover (which was sort of a mild anti-acid experience; slightly lower abstract reasoning ability, low energy, slight negative subjective affect) for 1-3 days of decreasing intensity – but only if I wasn’t physically active during use. If I was physically active, no hangover.

      • Orphan Wilde says:

        Addendum: Another possibility is that smoking/vaping was preventing the hangover effect, as I quit nicotine at around the same time I stopped being active.

    • Simon says:

      I usually had a pleasant afterglow for a couple of days, also a slightly vacant feeling. If you’re stupid enough you can double the dose on day 2 and it will be effective, though somewhat less so than originally. Diminishing returns. Same with smoking DMT although that tolerance seems to wear off between 30 and 60 minutes. MDMA midweek crashes always much more emotionally fraught.

  53. Doug says:

    This sort of thing is why my Dad avoids all kinds of drugs (cough syrup, tylenol, caffeine, you name it) as much as possible. If you can get by without, you don’t need to worry about any of this.

    • MawBTS says:

      I used to feel that way. Then I started taking modafinil, and can report results not far short of “life changing”. Sometimes you don’t know what you’re missing.

      • Anonymous says:

        Care to share what you are taking it for and why it was life changing? It’s a rather rarely prescribed drug that some use as a nootropic, so I’m curious if that’s the capacity you are taking it in or if you have narcolepsy.

    • Squirrel of Doom says:

      Did he ever throw you out with the bathwater?

    • Anonymous says:

      Not using cure X at all because doing so will make it less effective in the future is throwing the baby out with the bathwater, yeah.

  54. Squirrel of Doom says:

    Words I didn’t understand:

    · downregulation
    · potentiate

    • Murphy says:


      A decrease in the number of receptors on the surface of target cells, making the cells less sensitive to a hormone or another agent. For example, insulin receptors may be downregulated in type 2 diabetes.


      increase the power, effect, or likelihood of (something, especially a drug or physiological reaction).
      “the glucose will potentiate intestinal absorption of sodium”

  55. Jack V says:

    This is probably over optimistic, but is it possible tolerance is more likely for effects which are not “normal”, but medicinal use tries to put you back into a “normal” state when acclimatisation is more likely? To explain the apparent “the drug read the FDA approval” effect?

    • Cadie says:

      Could be a partial explanation, along with dosage considerations.

      Alice takes drug X medically because drug X raises levels of Y and Z, and Alice’s Y is too low. She now has normal Y – excess Y isn’t causing problems because she doesn’t have an excess. Her body might reduce the number of Y receptors she has, if it had made extra due to chronically low levels of Y and her body trying to get the most out of what little was there – but they probably won’t go below a healthy person’s amount. Her Z is only mildly elevated, causing some side effects. The slight elevation causes her Z-receptors to reduce gently and the side effects decrease, possibly going away. This happens whether she likes the side effects or not. She’s still getting most of the positive effect of the Y increase.

      Betty takes drug X recreationally. Her dose is higher than Alice’s, and her Y and Z levels rise well above normal human amounts. Betty is having all sorts of downstream effects from an overload of Y AND an overload of Z, and her body quickly adapts, reducing or increasing various receptors and changing neurotransmitter output. Her Y-receptors and Z-receptors both drop in number; she’s less sensitive to Y and Z now, and she keeps needing to increase her dosage to feel the effects she wanted X for in the first place.

      Except for the dosage difference, this won’t apply well to drugs meant to correct a short-lived problem, like opioids prescribed for post-surgical pain, but it would for most ordinary psych meds that one takes long-term. And dosing matters, because high doses cause more and faster changes.

      Another thing: many meds have different affinity for different kinds of receptors. Effexor is a great example of this: at low doses, it’s mostly an SSRI because it binds more easily to serotonin receptors and most of the effect is on those. At medium doses, it’s already filled most of the serotonin slots, and the additional medication molecules stick more and more to noradrenaline receptors, their second choice. Now it acts like a true SNRI. At very high doses, it affects dopamine too, though most therapeutic use is less than that.

      Recreational use of many meds, being higher, means that the drug in question can start affecting things it wasn’t intended to, because the molecules’ preferred targets are already full. So high doses can overload and ultimately reduce the number of a kind of receptor that therapeutic doses won’t simply because normal medical doses don’t affect the relevant receptor enough to do anything.

  56. I vote for the theory that medicine is usually prescribed in lower doses than drugs people take for pleasure. People don’t generally take just enough heroin to feel a little bit better in their day-to-day interactions, or to dampen their anxiety, or to concentrate better, as people do with many prescription drugs. Rather, they take enough heroin to feel REALLY GOOD RIGHT NOW and for the next few hours or so. I assume that the heroin is essentially a massive onslaught to the brain, all at once, followed by the body purging out the chemical and returning to some kind of a-heroinic state. By contrast, most medications seem to be prescribed in small quantities once or twice a day, so that you don’t get much in the way of high or low, but instead maintain an even amount over time.

    To use a metabolic comparison: both carrots and ice cream are made of the same essential stuff, sugar, which breaks down into glucose, which powers your cells and triggers the release of insulin. But the sugar in a carrot breaks down much more slowly than the sugar in icecream. Digesting icecream therefore, as I understand it, causes a large glucose spike in the blood, followed by the release of lots of insulin. Eating carrots results in a very gradual increase in blood glucose and thus insulin. And this difference has a big effect, of course, on how diabetics (I and II) and hypoglycemics handle ice cream, though pretty much everyone can eat carrots without too much worry.

    • Gbdub says:

      I was thinking along a similar line – with street drugs you’re basically encouraged to chase your tolerance, constantly increasing the dose to get the same high.

      Where’s with adderall or something, you stay on the same dose long term unless it really stops working, and even then you have to go to the doctor and convince them to up your dose.

      Maybe on a given dose you get a certain tolerance and no more? What if what we think of as “tolerance” is the baseline reaction, and “getting high” is more like “intolerance”?

    • Lumifer says:

      both carrots and ice cream are made of the same essential stuff, sugar

      Nitpick: bad example. Ice cream is mostly fat, not sugar, and whatever sugar it has is usually simple sugars which are readily absorbed. Carrots have a lot of cellulose and starch which needs to be broken down into simple sugars first. And for the equivalent amount of sugar you need what, one teaspoonful of ice cream vs one whole carrot?

  57. spookyskeleton says:

    A friend of mine seems to have self-induced the third effect (‘supposed to have effect X, but after a while it overshoots and has effect anti-X’) in response to actual orgasms. Some kind of pornography addiction in teenage years, and now his orgasms have a profoundly negative effect for him (inability to experience pleasure and that sort of thing apparently) so he mostly avoids them.

    I thought it sounded like a case of a neurotic or conservative belief-system/sexual hang-ups, but he doesn’t seem hugely afflicted by those things, and there are other people online saying similar kinds of stuff. Is this what would be predicted by the tolerance models?

    • Deiseach says:

      Cheap’n’cheerful explanation for that effect which I’ve seen floating around: it’s a case of conditioning. You can select from the palette of options porn presents you with to achieve your perfect situation – whether that’s body type, set-up, what acts are performed, etc. – and then you masturbate with that set-up and you condition yourself so that you only get satisfying orgasms when all the pieces are in place.

      Masturbation without your preferred set-up and even sex with another person are not as satisfying because it’s not the perfectly-controlled and tailored fantasy situation that you’ve conditioned yourself into responding to, so the feedback loop sets in: sex outside of the porn set-up is unsatisfying so you don’t engage in it as much so you never break the conditioning. And if your sexual experiences start with, or are mainly achieved using, porn – as they would with teenagers – then the conditioning goes deeper and there is less opportunity to have non-porn sex that counterbalances the fantasy sex and gives you a broader range of real world experiences.

  58. AleksiL says:

    I’ve been on methylphenidate to treat my ADD for a year now. My tolerance suddenly increased after a few months to the point where my dosage had to be doubled to keep having the intended effect. After a few weeks, my tolerance went back down to the point where the doubled dose was clearly too much and I went back to the original dose. It has been working well for me since.

    I ran out of a magnesium supplement shortly before my tolerance originally shot up, reintroduced it, had another break from it that coincided with another worsening of my tolerance, then noticed the coincidence and increased my daily magnesium intake to see if that helps. My tolerance started going back down soon after.

    My experience is anecdotal, but there are articles suggesting that magnesium and magnesium deficiency may play a role in both attention deficit disorder and stimulant tolerance development. I wouldn’t be surprised if nutrition and other lifestyle-related factors turned out to play a role in other cases, too.

  59. Kodos says:

    Our understanding of thr brain is at the level of stone tools and bearskins [to reference Spock from The City On The Edge Of Forever.] We know enough about the human brain right now to give us some insight as to how much more needs to be learned.

    Psychoactive drugs are blunt interventions. The finding the right drug regimen is a process of trial and error — and it’s mostly error. Months of error.
    Trendy (on patent, lots of advertising, get tried first). But most people will find a solution for themselves.

    The Classic drug class of MAOI’s are the best: Nardil, Parnate, Emsam. “Cheese effect” and dietary restrictions are overblown (Emsam, as a patch, provides some protection). Risk of hypertensive episode is low, and the best course is to not treat it (the treatment can be more harmful).

    I recommend you look at the work of Dr. Ken Gillman He publishes a “modern diet” on his site.

    Don’t prescribe XanaX — it comes down too quickly — and only Family doctors and GPs prescribe it. As a psychiatrist, you should be prescribing Klonopin.

    • Scott Alexander says:

      I’m a fan of Dr. Gillman and have written about MAOIs before. Curious what’s gotten you thinking that direction, though.

      Xanax is sometimes useful for panic attacks and other things where you need short-term but immediately-acting coverage. Also, some people have idiosyncratic reactions to one benzo but not another. Otherwise I agree that Klonopin is usually better.

      • Cadie says:

        Does very low natural blood pressure protect against dangerous blood pressure spikes due to MAOI/tyramine interactions? Even if they’re not as common as previously thought they do apparently happen sometimes. Looking at Wikipedia it seems that the tyramine pressure response is marked by a systolic increase of 30 mm/Hg or more. If your normal systolic BP is 90 with stimulants and 80-on-a-good-day without, could you safely eat a little more tyramine-rich foods on MAOIs than someone with normal or high BP? Seems like it would take more to cause a severe reaction as opposed to nothing or a mild one, and blood pressure spike on the lower end wouldn’t make you actually hypertensive the way it would a normal person, but I’m not sure how it really works.

        I’m not on MAOIs, and if they were under consideration I’d be asking my psychiatrist for all the info, so this is for curiosity. (And, well, if the answer is good I’d be more likely to discuss it further with her once I get some kind of health insurance and can afford more frequent visits. I’d be willing to give MAOIs a shot, especially if I had a bit of extra natural protection.)

        • InfiniteJester says:

          I wrote a comment above above about MAOIs and the hypertensive risk but think it should probably go here instead, apologies for the duplication.

          Public service announcement: it is criminally little-known, but taking a NRI like atomoxetine, bupropion, or desipramine along with an MAOI basically eliminates the chance of a hypertensive tyramine reaction (but NOT serotonin syndrome). I’ve been on all three along with both Parnate (160mg) and Nardil (120mg) and eat/drink whatever I want, including high risk foods, with zero even minor transient elevations in BP.

          Makes the fact that MAOIS are already so underprescribed even more criminal.

  60. Murphy says:

    At least with alcohol addiction there’s some known factors: having a really good version of alcohol dehydrogenase helps a lot.

    Perhaps there are equivalent genes for some of those other drugs. If you have the particular set of genes your body may or may not be able to handle the substances differently.

  61. MawBTS says:

    Can you have an addiction but no withdrawal symptoms when you go cold turkey?

    Once, there was a flash game called Desktop Tower Defense. I couldn’t stop playing it. I’d always have it in a hidden browser tab, obsessively playing it with every spare moment. At the time, I would have said I was addicted.

    Then, I erased my browsing data (for unrelated reasons), and… just kinda forgot about it.

    There were no withdrawal symptoms. No intrusive thoughts. Not even an impulse to replace it with a different game. Just a clean break.

    At one point I was bored, decided to play the game, and realised that I didn’t remember the URL. And I realised something else – I didn’t care enough to search for it on Google.

    My (layperson’s) understanding of addiction: pleasant experience –> excitatory neurons fire –> dopaminergic neurons respond by releasing dopamine –> “I like this! Give me more!” response. The more you expose yourself to the pleasant experience, the stronger the connections between the excitatory and dopaminergic neurons become – standard Hebbian stuff. Eventually the “Give me more!” response is so strong that you’re left with long-term potentiation (ie, addiction.)

    Are there non-Hebbian circumstances where this adaptation does not occur? Where neurons fire together but DON’T wire together – and you can enjoy something without habituating yourself to it?

    • I think I’ve heard of this happening in the experiments where they hook up a lever to an electrode on a rat’s nucleus accumbens. The rats will keep pressing the lever all day to get more reward until they collapse from exhaustion once they start, but won’t initiate the behavior of pressing it on their own, even after being introduced to its effects.

    • LCL says:

      I played Desktop Tower Defense and can understand getting unreasonably hooked on it for a while, especially if having little prior exposure to tower defense games. The game mechanics of a good TD are like a super-stimulus for whatever kind of mental modules make us good at things like engineering or coding – visualizing how a bunch of parts with specific properties have to fit together in a particular pattern to form an emergent, functional system. And Desktop Tower Defense was a good TD.

      I also had an indefinite period of time, during the brief window when synthetic cannaboids were available and not yet illegal, when I did almost nothing but use JWH-018 continuously, order in food if hungry, and play the Bubble Tanks Tower Defense games. This could have been anywhere from a couple days to nearly a month; time lost relevance. I’d predict about a week, with low confidence. It ended when I finished all the content.

      I remember it as the most prolonged period of contentment I’ve experienced – I was totally satisfied to live inside those games indefinitely. Though the knock-on effects on for my offline life were predictably destructive, I still can’t help thinking of the period fondly.

    • Justin says:

      This is my experience with almost any game I am “addicted” to. sometimes I force myself to stop, sometimes I just stop playing from one day to the next. I never go back unless I deliberately decide to. But while playing, it consumes all my attention over the course of days or weeks, and I can’t stop easily. I don’t have any experience with substance addiction; nothing I’ve tried gave me impulse to try it again.

  62. Moderately Opaque says:

    I am seeking literature on the subject of long-term negative effects of stimulant use to treat ADD.

    Here is a story that I am sure is very familiar to many SSC readers:

    I am a early/mid 20s male, 3-4 standard deviations above average intelligence, working in software. For the last decade – if not longer – I have been plagued by something I can only describe as “lack of willpower”. I do not experience hyperactivity/mania. I have undiagnosed mild cyclical depression (that I am not particularly interested in treating chemically). I am otherwise mentally healthy, as far as I can tell. I used to refer to this “lack of willpower” as “laziness” until I found certain internet communities (including LW/SSC).

    A few years ago I took Vyvanse twice to assist in studying for an accreditation exam (very math heavy). While on normal days I would be able to do 2-3 hours of studying before giving up, on the days when I took Vyvanse (spaced a week apart) I was easily able to study 10-12 hours. It felt completely effortless to make myself do so, rather than extremely difficult. Simply deciding that it was what I was going to do was enough. If this effect is persistent, it would represent an enormous improvement in my quality of life, especially if there is a way to deal with the side effects (lack of hunger and extreme difficulty getting to sleep – I suspect the dosage was too high).

    My drug use history, if relevant:

    Weed: used anywhere from 1-5 times a month from the ages of 18-20, tapering off sharply as it went from being pleasant to giving me headaches and/or putting me to sleep, with little in the way of positive effects. Haven’t used in a year, at least.

    Nicotine: ~1 cigarette a day for 3 months starting at age 19, switched to vaping fairly easily, though would smoke analog socially. Quit vaping after about three years, after reducing dosage several times. Nicotine was pleasant throughout but did not notice any particular increase in productivity/willpower.

    Caffeine: Anywhere from several times a week to once a month depending on availability/desire. Been cutting down recently due to digestive issues and heartburn. Did not notice any increase in productivity/willpower.

    Alcohol: 2-3 times a month, 95% social, always when eating. Generally pleasant if I stick to the good stuff and don’t overdo it. My tolerance is fairly low and hasn’t changed.

    Anyways, my main concerns are long-term effects like reduced intelligence/plasticity, especially if permanent, and tolerance. Vyvanse felt nice for a few hours but not the entire time the effect lasted (mostly neutral, until I couldn’t get to sleep, then negative due to tiredness). The “niceness” was not as strong as with weed (when I enjoyed it) and alcohol, if longer lasting. I do have an “addictive personality” in some respects, but my drug use history has basically been “start taking drug, then reduce dosage until quitting” rather than the opposite, so I am not terribly worried about getting hooked on it recreationally.

    Any literature/advice (non-medical), beyond speaking to a psychiatrist?

    • Piglet says:

      Ditto this request. I have a child recently diagnosed with ADHD, we are considering medication, and I can’t for the life of me find any information that appears even vaguely reliable on the potential long-term downsides (or indeed even efficacy) of such medication.

    • Adam says:

      My wife is a hardware engineer, don’t know her official SDs above mean but 1500+ on the old 1600 SAT scale, top school, has worked on classified programs her entire career. Seems pretty smart. She’s been on Adderall for ADHD for over a decade and it does not seem that she has gotten stupider or less plastic. She’s an anxiety-riddled mess, which I suspect amphetamine use does not help, but given her personal history, I doubt drug use is the cause of this or at least the sole cause.

      Vyvanse does nothing for her, by the way. Which medication works for you is going to be a trial and error matter. It took years before they even correctly diagnosed the ADHD. They mostly thought it was depression before that, but as it turns out, being perpetually crappier at things you do than you should be because you can’t concentrate is kind of depressing.

      • Anon9 says:

        For what it’s worth, I take Adderall for adult ADHD, and I too was an academic overachiever and am an anxiety-riddled mess, and I was wary of it too because prima facie it doesn’t sound ideal for someone with chronic anxiety and chronic insomnia, but it turns out the Adderall has a mild but palpable anti-anxiety effect for me. Certainly it doesn’t make the anxiety worse. Also, I can take an Adderall and half an hour later feel sleepy and take a nap, and I’m a person who hadn’t been capable of napping since babyhood.

        As another data point on tolerance, though, I’ve been on Adderall now for three years for what in 20/20 hindsight is clearly legit ADHD and I have had to raise my dose slightly just in the last two months to recapture the full executive function effect. (I have an Rx for twice what I’d been taking on $ grounds, and use the short-acting kind for adjustability. I’m up from 45-60 mg to 60-75 mg cumulative per workday. I don’t always take any on weekends.)

    • Anonymous says:

      I have the primarily inattentive version of ADHD and was just considering whether to try prescription ADHD meds. Currently I take caffeine in the form of 1-2 double espressos daily and synthroid. (Also tried taking maricopa, but failed in remembering to take it regularly.)

      I wasn’t sure whether stimulants would be helpful for my version of ADHD, but Anon9 here is giving me hope. I would love to hear from anyone else who has had success (or failure) with rx stimulants.

      • Adam says:

        I believe my wife’s is primarily inattentive and the Adderall definitely works. She has tried other medications and they did nothing, including Modafinil that one of Scott’s readers convinced her to try. It’s certainly a stark difference from the outside. Unmedicated, say we’re out shopping. She just disappears, wanders off, and I’m constantly running around looking for her. We can’t watch television together because she’ll just get up and wander away every few minutes. She visibly cannot concentrate on anything. With Adderall, she’s a completely normal person. It doesn’t even have a stimulant effect. She still drinks coffee to actually wake up in the morning.

      • Cadie says:

        They have been a tremendous help with ADHD-PI for me. I couldn’t take Strattera because it caused severe nausea, but Adderall didn’t do that. The side effects were mostly mild and transient – a few days when it was hard to fall asleep, and low appetite for awhile resulting in a total loss of 10 pounds (which wasn’t a big deal and I was able to gain it back without overshooting anyhow.)

        Not a doctor etc. but I think stimulants have a bad reputation that’s a bit unfair, possibly because they DO get abused and misused a lot, and can be dangerous in overdose or mixed with the wrong things. But they’re sometimes very helpful for people with a medical need – that’s exactly the population they’re produced for. And therapeutic prescribed doses are much safer than recreational ones. When taken responsibly and treated with respect they can be a useful treatment, and a good psychiatrist can help figure out if they’re safe to try (usually yes, not always though) and if so how much.

        One thing I would suggest if you do get a prescription for a stimulant is to reduce your caffeine intake, even if you aren’t at risk of blood pressure getting too high. The effect of new stimulants plus one’s usual caffeine feels like an overload. The prescribing doctor can give you more individualized info; chances are you won’t need to cut caffeine out entirely, especially if you start on a low dose of meds, but drinking less coffee if/when you begin is probably a good idea.

      • Anonymous says:

        Also, that should be Bacopa. I was not actually taking the Arizona county to treat ADHD symptoms.

      • Joyously says:

        I was prescribed Ritalin for ADHD several months ago and I hate it. The first time I took the entire dose I had been prescribed, I felt unpleasantly wired, like I could almost feel my heart beating. My hand tremors got worse. My doctor said I could try cutting the pills in half, which helped with the side effects, but I’m not sure it helped my concentration all that much. Lately I’ve been taking one pill when I really need to work on something and just suffering through the weird sort of crunchy feeling in my mind and body, which I still hate. (This experience has extra convinced me to never ever take stimulants recreationally, by the way).

        I also have chronic insomnia, but whatever effects the Ritalin would have on that were balanced out by Seroquel, which I love and I want to hug it and kiss it and take it forever.

        • Anonymous says:

          If my ritalin ever made me feel like that, I would be asking about dexedrine. My (non-expert) understanding is that some people find ritalin unpleasant in the kinds of ways you describe, and although one might have the intuition that actual amphetamine would produce even more of those same undesirable effects, it is pretty common to have a bad response to ritalin but tolerate dexedrine quite well.

      • Anonymous says:

        Regarding the “primarily inattentive version”, is this still even a thing? I had heard it said, before DSM-V came out, that the subclassifications of primarily inattentive, hyperactive, and combined were going to be abandoned in DSM-V. I don’t know what actually happened (and am evidently too lazy to google it myself), but at any rate there are definitely some prominent people in ADHD research that consider it to be only a single disorder (or, that the sub-classification scheme is not useful enough to bother with, at least).

        All of which to say, if you’ve got ADHD-whatever, stimulants may be very beneficial for you.

        • Anonymous says:

          In the previous edition, DSM-IV TR, the three types of ADHD were referring to as “subtypes.”
          This has changed; subtypes are now referred to as “presentations.” Furthermore, a person
          can change “presentations” during their lifetime. This change better describes how the
          disorder affects an individual at different points of life.

          [From this pdf]

          Setting aside how prominent people may look at it, I can’t think of a better way to describe my ADHD, which involves no hyperactivity at all.

  63. utilitarian troll says:

    I understand that in many cases you can block the development of drug tolerance through cycling drugs on and off.

    I’m glad that you wrote this post, because I had been reading about tolerance myself and I was getting confused, but I assumed it was just because I was a non psychiatrist.

    Here are some highlights from my notes on low dose naltrexone in particular. First, the low dose form and the regular dose form don’t need to have the same effects:

    Basic science evidence supports that concept by showing that low- and high-dose opioid antagonists have quite different impacts on the physiologic system [43].
    It may initially seem strange that a medication can have an opposite effect when given at a low dosage. However, there is a strong precedent for this concept—and with opioid-related drugs in particular. A paradoxical hyperalgesic effect of low-dose morphine was first widely reported in 1987 [44]. Morphine was administered via the IV route to rats after arthritis was induced using Freund’s adjuvant. A dose of 100 μg/kg produced clear analgesia, 50 μg/kg produced less significant analgesia, and 30 μg/kg showed no difference from saline. At around 10 μg/kg, however, the researchers saw the development of morphine hyperalgesia, which became most pronounced at 6 μg/kg. This finding, which has been replicated several times (e.g., [45]), suggests that there is a small window at which opioid analgesics produce the opposite effects than those typically expected. The dosage of morphine that appears to cause paradoxical hyperalgesia is approximately 1/10th of the dosage typically used to produce analgesia. We note that the dosage of naltrexone that is used to reduce pain is also approximately 1/10th of the dosage used for substance abuse treatment.

    The “Sinclair Method” is a treatment protocol for alcoholism where you’re allowed to drink alcohol whenever you want, you just have to take naltrexone first to block the rewarding effects. (Nevermind that seemingly authoritative sources like say you should definitely *not* be combining naltrexone and alcohol!) Interesting paragraph from a Sinclair advocacy site:

    Naltrexone or nalmefene offer a window of opportunity for pharmacological enhanced learning of healthy behaviours. If you last took the medication of a Friday afternoon, Saturday is a washout day, when the medication is being removed from your body. Starting Sunday afternoon, roughly two days since your last dose of naltrexone or nalmefene, you are in a state where patients report that doing those alternative behaviours is especially reinforcing. A highly flavoured meal tastes great. Even the first bit of chocolate is fantastic. Sex is more rewarding. Exercise feels marvellous. The supersensitivity gradually disappears over the next few days, so it is wise to make an effort in the healthy activities during this window while you get more reinforcement.

    This source seems to corroborate the view that naltrexone’s psychoactive effects are of multiple days in duration (re multi-day “washout period”):

    selective κ-opioid antagonists have been known since their initial development by Portoghese and Takemori more than 20 years ago to have remarkably long durations of action. Although this property might be considered a therapeutic advantage (as infrequent dosing may be sufficient and missed doses would be less concerning), the lack of understanding of its basis has slowed drug development. We recently reported (Bruchas et al, 2007; Melief et al, 2010) that the long action was not a result of κ-receptor downregulation or drug persistence, but rather that these ligands were not truly competitive antagonists; instead their effects were caused by the activation of c-Jun N-terminal kinase (JNK) following κ-receptor binding (Figure 1).

    I’ve tried LDN myself, and I think I can confirm that some of the interesting effects lag several days behind consumption.

    So Naltrexone is maybe a weird example that’s best not generalized? Anyway I’m still really confused.

    • Scott Alexander says:

      Very interested in hearing anything else you know along the same lines.

      (what are you taking LDN for? Did it work?)

      • utilitarian troll says:

        Very interested in hearing anything else you know along the same lines.

        Oh boy, senpai noticed me!

        Well here’s something interesting. Wikipedia says that Naltrexone is a κ-opioid receptor antagonist. And if you read the page for κ-opioid receptor agonist, they’re implicated in drug addiction. If I’m reading this correctly, the agonists are supposed to work similarly to the way LDN (supposed antagonist) works? “heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects[74] and by causing the curative effect of up-regulation (increased production) of MORs[75] that have been down-regulated during opioid abuse.”

        (what are you taking LDN for? Did it work?)

        Upregulating my reward system to make it more fun to socialize with people. Check this research dawg. I haven’t collected much data, but preliminary observations seem consistent with the hypothesis that LDN increases my social anxiety in the short term and relieves it with chronic use.

        Was there something in particular you were curious about? I’ve done a lot of reading on this topic, and I’ve become a lot more social over the course of my experimentation. But it’s tough going with my complete lack of a neuroscience background.

    • “The “Sinclair Method” is a treatment protocol for alcoholism where you’re allowed to drink alcohol whenever you want, you just have to take naltrexone first to block the rewarding effects. (Nevermind that seemingly authoritative sources like say you should definitely *not* be combining naltrexone and alcohol!)”

      Couldn’t it just be that people tend to drink more while taking naltrexone to try to get the rewarding effects, to the point where they get alcohol poisoning?

      Also if the reports of increased reward are true, why is naltraxone not routinely prescribed as an antidepressant or general life enhancer?

      • Berna says:

        Yeah, that sounds really interesting. Maybe I could teach myself to enjoy exercise!

        • K says:

          Interesting! I was reading the comments on tolerance above, and thinking that, yes, you develop tolerance to everything if exposed to it enough – even your favorite food, music, or sex. But I wonder if it cuts both ways?

          Lately (meaning for some years), I have gradually and increasingly taken up exercise. At first, it’s a chore, I really needed to force myself to go for a run, or whatever activity I set out to do. But now I kinda enjoy it, even really boring stuff like running along a road. Possibly, this just mean I’m getting in better shape, but on the other hand, I try to push myself as hard as before – so maybe I have developed a kind of “tolerance” to the negative reinforcement?

      • Scott Alexander says:

        Increased reward is only briefly while you’re coming off it. Like I said, I suspect decreased reward the rest of the time, but there’s no proof or even anecdote.

        • utilitarian troll says:

          Increased reward is only briefly while you’re coming off it.

          How sure are you about this? There seem to be anecdotal reports of e.g. persistently elevated libido among long-time male LDN users online. This study even found some patients had their ED issues permanently fixed after a course of naltrexone. (“A two-month follow-up, at which time patients were off treatment, erectile capacity had returned to baseline in 10 patients, while five reported complete recovery of their sexual ability.” Maybe the remaining 10 had their condition return to baseline because they were porn addicts.)

          Note that regular-dose naltrexone, not low-dose, was used in the aforementioned study. (My hunch is that the effects are pretty similar.)

          If we consider the reference class of hormetic stimuli, it wouldn’t be surprising if there were interesting effects that persisted with use:

          * Lifting heavy weights will make you weaker in the short term, but your muscles will get stronger in the long term as a hormetic effect. Your muscles will continue to stay strong no matter how long you continue lifting. If you stop lifting, your muscles will fade (very gradually).

          * Drinking alcohol will decrease anxiety in the short term. But if you drink too much too frequently, you’re an alcoholic, and one of the symptoms of alcoholism is increased anxiety–presumably a hormetic effect. I’d expect elevated anxiety to stick around as long as you continue to be an alcoholic, and gradually fade if you quit drinking.

          BTW, Scott probably already knows this, but for the benefit of readers: LDN is typically taken before bedtime so you experience the miserable effects while you sleep. (I’ve experienced them while waking though, and they didn’t seem that bad to me–kind of enjoyable actually. Like I said it’s a confusing substance.)

          • Dave Kinard says:

            I have some LDN. I might take it eventually. But first I haveto get off of .5mg of suboxone (not for addiction, for extremely treatment resistant depression, comorbid with AS, which is an auto-immune inflammatory disorder that causes chronic pain). Some interesting things have been going on recently.

            Anyway, I thought it worth mentioning, for anyone here- if you have used opiates recently LDN (yes even low dose) is a good way to get yourself in the ER. The study Scott was referring to about combining Naltrexone with Opiates was not LDN, but Ultra low dose Naltrexone- near homeopathic doses- which has different effect then LDN, which has different effects then N.

            The ULDN seems to work through effects on the delta receptor- LDN hs effects not only on the mu and kappa, but on Opiod Growth factor- which effects the proliferation of opiate receptors AND has immuno-regulatory effects. Some folks use it help with thei auto-immune disorders.

            On the subject of Scott’s original question, the brain and body have a tendency to reuse the same chemical messengers for many different purposes- so effects are always going to be messy and complicated.

            I could go into more detail later, but it’s late.

            PS. No offense to Scott, but most P-docs don’t have a clue how the drugs they are prescribing work. As a patient, I am usually better informed then the doctors I meet. Which makes some sense. To them it’s just a job. To me it’s staying out of the ninth circle of hell (there are circles, and no matter how bad it gets, there’s always some place lower)

          • utilitarian troll says:

            PS. No offense to Scott, but most P-docs don’t have a clue how the drugs they are prescribing work. As a patient, I am usually better informed then the doctors I meet. Which makes some sense. To them it’s just a job. To me it’s staying out of the ninth circle of hell (there are circles, and no matter how bad it gets, there’s always some place lower)

            Fascinating. So who *is* informed on these drugs? If anyone.

      • utilitarian troll says:

        Also if the reports of increased reward are true, why is naltraxone not routinely prescribed as an antidepressant or general life enhancer?

        Well first, conditional on naltrexone being an effective treatment for this purpose, do we expect the medical establishment to prescribe it? I would not. They’re not even prescribing it for Multiple Sclerosis.

        My hunch is that the increased reward thing *does* work, and this partially explains why the drug is touted as a miracle cure for such a wide variety of ailments online. Users experience enhancements of their reward systems and fall prey to an affective death spiral. (I’m not actually sure affective death spirals are a thing, but you guys are Less Wrongers, so that link will convince you, right?)

        My other hunch for why it’s touted as a miracle cure is that it actually is a miracle cure. In the same way elevated stress makes a wide variety of ailments worse, upregulating the reward system (and–indirectly–the immune system) makes a wide variety of ailments better.

        Note that I am a mere dilettante and my hunches should be taken with a gargantuan grain of salt.

        • Dave Kinard says:

          It has direct impact on hormones that regulate the immune system, which also regulate opiate receptors.

          That said, while a lot of people find it makes their ailments better, others find it makes them worse. This is especially true for depression and anxiety. And small changes in dosing apparently can swing it the other way. So… yeah.

      • Loquat says:

        Neither nor wikipedia explains *why* combining naltrexone and alcohol might have bad results, but they do both say that trying to use opioids while on naltrexone can be a bad idea because a user who really wants to get high might take way too much in an attempt to override the suppressing effect of the naltrexone and wind up overdosing.

        (Kind of a lot of the problems listed on Wikipedia’s naltrexone page seem to stem from the user going “screw this treatment, I need to get high”.)

        I have an alcoholic in the family who’s been using the Sinclair method for over a year now – take naltrexone before drinking, never touch it otherwise – and he’s had great success with no serious side effects. Notably, he’s been able to cut down from drinking almost every night to drinking only a few times a month, with an accompanying reduction in naltrexone use.

        • Dave Kinard says:

          Taking it after going off opiates can result in a super acute withdrawal-including dangerous elevations in blood pressure, possibly leading to hypertensive crisis-similar to the MAOI “cheese” reaction (which, having been on MAOI’s, you actually need to consume a helluva lot of tyramine, not likely to happen from cheese, soy is more likely culprit)

          • InfiniteJester says:

            Public service announcement: it is criminally little-known, but taking a NRI like atomoxetine, bupropion, or desipramine along with an MAOI basically eliminates the chance of a hypertensive tyramine reaction (but NOT serotonin syndrome). I’ve been on all three along with both Parnate (160mg) and Nardil (120mg) and eat/drink whatever I want, including high risk foods, with zero even minor transient elevations in BP.

            Makes the fact that MAOIS are already so underprescribed even more criminal.

   has more info.

  64. Some Guy says:

    Speaking of tardive dyskinesia, during the Republican primaries, I came across a website claiming that John Kasich had facial ticks that could be explained as tardive dyskinesia.

    I’m not an expert, but now,every time I watch an interview with him he regularly makes weird faces.

    What are the odds that he’s got tardive dyskinsia, and if so, does this mean he’s been on powerful antipsychotic?

    • I get involuntary muscle twitches if I’ve had too much coffee as a result of not enough sleep or if I’m around really unpleasant, stressful people for a long time. I don’t know anything about tardive dyskinsia, but “too much coffee, not enough sleep,” seems like a really likely thing for almost anyone on the campaign trail.

  65. Paul J says:

    I think the SSRI’s are a completely different sort of case from the benzos and opioids, etc. In typical case of SSRI therapy, it’s only after homeostasis has worked it’s magic over a period of weeks that the therapeutic effect emerges. You might say that “tolerance” to the SSRI is the therapeutic effect, so to speak. Tolerance to the immediate physical effects of the drug.

    • Scott Alexander says:

      Yeah, I’d heard this theory before (though I can’t find an exact source for it now). But I’m trying to figure out what that means. Is this a case of overshoot/antitolerance like the tardive dyskinesia, where the serotonin receptors become so overstimulated that increasing serotonin via SSRIs means there’s less serotonergic transmission? If so, is tardive dysphoria a double overshoot? That is, you increase serotonin in order to decrease serotonin, but decreasing serotonin ends up actually increasing serotonin? That would be so annoying.

      But recently I heard that the reason SSRIs need a month to work is actually because there are serotonin autoreceptors that counteract normal serotonin receptors, and for some reason those develop tolerance after a month and stop counteracting, but the normal serotonin receptors don’t develop tolerance and keep acting. Which is also pretty annoying.

      • Paul J says:

        I’d heard that the increased serotonin due to the drug leads to down-regulation of the post-synaptic 5HT receptors and that this process takes several weeks. But whether it is this particular reaction that is responsible for the therapeutic effect, or one even further downstream, it still seems that, abstractly considered, you induce a perturbation in the system (taking the drug), which is followed by a homeostatic response in the system that counters this new reality, mitigates it. That seems like tolerance.

  66. Thursday says:

    Not just drugs but some experiences don’t seem to be subject to diminishing returns (much). I can listen to the same music, especially classical, for a heck of a long time before getting tired of it. Shakespeare and Homer don’t get old. Neither does Star Wars. I still enjoy looking at my wife five years later. I never stop enjoying sex. I could eat peanut butter and burritos (not at the same time) just about every day. Why doesn’t the dopamine hit I get from these things go down?*

    *I am aware that if I ate nothing but burritos or did nothing but read Shakespeare I’d probably get pretty sick of those things.

    • Ray System Pathee says:

      Check out the Metaphysics of Quality:

      Dynamic quality cannot be defined. It can only be understood intellectually through the use of analogy. It can be described as the force of change in the universe; when an aspect of quality becomes habitual or customary, it becomes static. Pirsig calls dynamic quality “the pre-intellectual cutting edge of reality” because it can be recognized before it can be conceptualized. This is why the dynamic beauty of a piece of music can be recognized before a static analysis explaining why the music is beautiful can be constructed.

      The burrito creates some powerful dynamic churn, enough so that the static waves of quality still feel pretty dynamic. But as you concede, eating only burritos every day you’d soon find yourself munching on static waves of blandness.

    • This reminds me of a study the army did back in the fifties about food enjoyment/boredom. They found that some foods, like IIRC tinned meats, tended to be enjoyed a lot the first time they were eaten, but decreased rapidly in enjoyment thereafter, whereas other foods, like milk and bread, could be eaten every day without any decrease in enjoyment.

      I suspect that we are basically really well adapted to drinking milk and eating bread (at least if you’re European. If you’re Inuit, substitute “fish.”) Our ancestors were probably selected for the ability to tolerate large quantities of these foods. Likewise, we have probably been selected for ability to enjoy lots of sex, our spouses, and heck, maybe even good entertainment. (Nah, I’m not going to suppose that there’s a “like Shakespeare” gene.)

      • Psmith says:

        Likewise, we have probably been selected for ability to enjoy lots of sex, our spouses

        The President and Mrs. Coolidge were being shown [separately] around an experimental government farm. When [Mrs. Coolidge] came to the chicken yard she noticed that a rooster was mating very frequently. She asked the attendant how often that happened and was told, “Dozens of times each day.” Mrs. Coolidge said, “Tell that to the President when he comes by.” Upon being told, the President asked, “Same hen every time?” The reply was, “Oh, no, Mr. President, a different hen every time.” President: “Tell that to Mrs. Coolidge.”

  67. DensityDuck says:

    Part of the problem is that nobody is willing to just give random amounts of psychotropic drugs to people who don’t describe themselves as suffering from depression in order to see how they react.

  68. DrBeat says:

    So, if you suspect you have tardive dysphoria, and that means you have permanent irreparable brain damage that means you will never ever ever ever ever ever ever as long as you live have the ability to feel happiness, THEN are you allowed to want to stop being alive?

    • Adam says:

      I wonder about someone like Junior Seau or Dave Duerson. We definitely know since they donated their brains for study that they were completely riddled with CTE, parts of the brain just basically gone that are never coming back. An NFL player is an absolute extreme example of repetitive head trauma, but we certainly seem to be learning that some people are just medically never going to experience pleasant lives again. It’s hard to see how anyone could reasonably oppose these two in their respective suicides. It’s not even just that they know they’ll never be happy, but there is a very good chance they’ll eventually exhibit extreme violence toward others they love. Why risk that to preserve a negative utility life?

    • DensityDuck says:

      Well, suicide is, y’know, squicky, so, no, you suffer forever because I’m not gonna be the one who said squicky was okay.

      Besides, I’m not sure I wanna live in a world where someone can be declared Permanently Unhappy and encouraged to hit the local Suicide Booth. Because, um, I was that guy and if suicide had been a socially-codified option I probably wouldn’t be posting this right now.

  69. Tom (Perth) says:

    I have a pet theory about myopia (near-sightnedness) that is similar to some of the paradoxical effects you mention.

    It has generally been assumed that myopia is caused by too much time focussing on near objects. My pet theory is that myopia progresses because of too much time with the eyes defocussed, whether too near or too far.

    Babies start off hypermetropic (long-sighted) so in normal conditions this feedback mechanism would only train the eyes towards normal vision; but if they become myopic for any reason, the same feedback mechanism would quickly make the vision much worse.

    Perhaps a similar mechanism is at play in supertolerance. There is a feedback mechanism that can only recognise “dysfunction” in general and always responds in one direction, even when that’s the wrong way.

    (Side notes: The trigger for myopia in the first place is too much time indoors and too much time wearing sunglasses: not enough light hitting the retina, which lowers dopamine levels in the eye, which allows the eyeball to grow too long. If these theories are correct, it is a mistake to undercorrect myopia, because that triggers more progression directly AND makes time outdoors less enjoyable!)

    • Ray System Pathee says:

      I wrote about my experience with myopia above, but your theory is very different.

      I played outdoors constantly as a kid, and I don’t think I owned a pair of sunglasses until I was in junior high, but I needed glasses by age 9 anyway. (Probably genetic: my mom and both her parents wear thick glasses. So does my twin brother.) My experience has been that undercorrecting my myopia, both by deliberately not getting the full prescription the optometrist recommends and by spending at least waking hour or so each day without my glasses on, has forced the muscles that bend my eye’s lenses to work harder and decay slower. I have my twin brother as a reference point: he hasn’t done these things and his eyes have decayed much faster.

      • Tom (Perth) says:

        It’s hard to argue with a walking twin study 🙂 I suspect your genetic set-point is myopic, but I think the rest may still apply.

        What do you do while your glasses are off? Are your eyes defocussed? I can’t imagine you would deliberately spend an hour a day with blurry vision.

        It’s a tricky area because it depends on behaviour. Say you spend a lot of time reading up close. If you’re perfectly corrected for distance then you would be defocussed when reading too close with glasses on, prompting more myopia. I think we would agree on that.

        On the other hand if you spend a lot of time looking further away, I say that the opposite (undercorrection or no glasses) would also cause progression.

        By the way, eye muscles aren’t involved in most myopia. It’s to do with the length of the eyeball, which can’t be changed with exercise.

        • Ruben says:

          Hey fellow pet theorists. Let us assume that the many studies that do not show that nearwork and time spent indoors explain myopia just failed because these things are hard to measure accurately. A big assumption.
          Now, plausible interventions can fail for two main reasons:
          1. the training is not carried out as intended: e.g. Undercorrected people just move the book or the device closer to the eyes/ stay indoors even more
          2. the training is just not on the same scale as the original cause: people work in doors with low ambient light for many many hours over their whole life, so training that are on the order of minutes or hours per day just do not counteract enough.

          The latter failure point is interesting because it makes interventions such as undercorrection and daylight lamps (or outdoor school or bigger windows) more likely to work, since they actually correct underlying cause/ scale.
          The former failure point is interesting because there is a lot of room for e.g. personality to affect how well do you adhere to the prescribed treatment, so undercorrection might work for conscientious people (who are also able to maintain good posture by force of will).

          Your point about how the eyeball adapts is interesting. Any references I could read?
          As for the point of the brain being back better at correcting, I think optometrists commonly obtain both physical and functional measures of myopia, It would be interesting whether these are discrepant for you.

        • Ray System Pathee says:

          The activities I perform without glasses tend to be pretty consistent from day to day:

          – make coffee (kettle + pour-over)
          – make & eat breakfast (usually a smoothie)
          – feed my kid breakfast
          – brush my teeth
          – shower
          – get dressed
          – eat lunch, sometimes while talking to someone across a table

          Objects I’m interacting with in these activities are a broad range of distances from my eyes, anywhere from 6 inches (checking the coffee grinder to make sure I got all the grinds out) to 60 feet (looking out the window while eating lunch).

        • switchnode says:

          What do you do while your glasses are off? Are your eyes defocussed? I can’t imagine you would deliberately spend an hour a day with blurry vision.

          I am moderately nearsighted and hardly wear my glasses at all unless I’m leaving the house. The interior of my home is so familiar that sharp vision really isn’t necessary to navigate it; unless I’m watching a movie on a big screen (rare) or looking for a small object, there’s no need to see the exact details of things I have seen the details of a thousand times before.

          Most of my time at home is spent reading or using the computer (or both), and for close work my uncorrected vision is as good or better and less strenuous than wearing glasses, so I generally don’t put them on without a reason.

          I always wear them when I’m going somewhere, though, even if it’s only down the block for some milk; not being able to see well in open environments puts me on edge.

    • dhill says:

      I’ll just provide another data point.
      When I was about 5 years old my mother (a physician) has seen me squinting with one eye, so she got me to an eye doctor. It turned out, the squinting isn’t that bad, but I have hyperopia. I started with 2.5+ glasses, which were gradually reduced to 0.5+ at the age of 18. The eye doctor recommended that I still wear them for a while, but I stopped, because I was doing sports a lot and it interfered.

      Then for some 7 years or so I went on without glasses. I studied computer science and went on to programming as my job. At about 25, I realized I’m a bit myopic. I had trouble seeing the road situation instantly, so I got myself -0.5 glasses as measured. I used them sparingly — while driving at night and after work, when my eyes were tired. But it got worse and they weren’t enough after a day at the monitor.

      I researched the topic a bit and realized that the eyes are straining when looking at close objects (and not the other way round, as I thought previously). After some research (more about it later), I decided to buy a pair of +0.5 glasses for use with the computer (they basically put infinity at 2m away).

      I’m still a bit myopic, but it didn’t get worse, maybe a little better even. I don’t have to wear glasses when riding, even after a long day at work. Wearing them while coding is much less of a hassle. I’d recommend this to anyone with slight myopia.

      Now the funny aside. When searching for alternatives for having to wear glasses while riding/exercising, I’ve encountered some conspiracy theory sites around the idea of correction glasses. When buying the glasses, the first vendor got into discussion with me about getting +0.5 glasses, when my measured myopia would point at -0.5 and took it personally, that I would ignore his advice. They have shown me few models, but ignored me for long enough, while serving other customers, that I decided to go somewhere else. I got my glasses in the next shop, telling them these were the numbers I got from the eye doctor, to avoid discussion. I think it’s just how the market works and that people selling, what I recommend here, get wiped out. It’s also my go-to example of how the conspiracy theories are born, now.

      • Tom (Perth) says:

        This looks like a decent summary, especially Figure 1 and the associated references:

        Interestingly, undercorrection is indeed associated with faster myopia progression in two prospective randomised studies. (Although we don’t know if that’s due to the defocus per se or a resulting change in behaviour.)

        The best known ways to slow myopia progression all work by slowing the elongation of the eyeball, either physically (ortho-k), chemically (topical atropine 0.01%), or indirectly (outdoor time leading to dopamine changes).

        Anyway my main point wasn’t really about myopia but about the possibility of feedback mechanisms that always push in one direction — they only respond to the magnitude of dysfunction, not the sign — and can flip into paradoxical behaviour if they go too far. The solution then is to reset conditions back into the normal domain.

  70. Sniffnoy says:

    (This seems true in general – I get euphoric effects from caffeine when I drink it very rarely; if I drink it more often, the euphoria goes away and I just feel a little more awake. This is important since it suggests tolerance isn’t just your body metabolizing the drug better, but actually a matter of receptor-level action – something I think everyone agrees is true, but which it’s always nice to have independent confirmation for.)

    Hm, I was under the impression caffeine had substantial tolerance to its stimulant effects, but just going by what’s on Wikipedia, it seems like you have to break down what stimulant effects you’re talking about to be able to say anything!

  71. The Nybbler says:

    Tolerance is often said to be a permanent thing; supposedly you actually lose receptors and they don’t come back. Is this true for any drugs or is this drug-warrior nonsense? I’ve never been a serious drug-user, but for caffeine, tolerance definitely seems to be quite temporary… if it’s not doing anything, I can quit temporarily and suffer through the headaches, and it’ll start working again afterwards.

    • Jayson Virissimo says:

      From my own experiments, both caffeine and nicotine tolerance can be diminished by taking extended breaks (weeks to months). Although, nicotine never has returned to quite the same level of effectiveness it had for the first few times.

      • Ray System Pathee says:

        Before I became a regular cup-a-day coffee drinker, any dose of coffee would give me this tightness in the back of my neck, an excited and nervous feeling in my gut, my thoughts moving very fast and with seemingly uncommon gracefulness from one to the next, etc. I enjoyed it, it was a kind of buzz.

        Now, I can suffer through quitting coffee for a few days or even a week or two, and then the first cup, if it’s really strong, gets me just a hint of the aforementioned symptoms. After that it’s like I never stopped–it just makes me feel slightly more awake.

    • Adam says:

      I’ve been using opiates for four years and my wife has been using Adderall for 12 years, and no, in neither case has the tolerance been permanent. And, of course, I periodically don’t drink alcohol for long periods of time, and definitely get drunk faster after that. I was a bar manager once a little over ten years ago and back then, it’d probably take 20 shots to do what 4 will do now.

    • dndnrsn says:

      My experience with stuff that builds tolerance is that some of it never goes away, and tolerance comes back quicker than it was built up in the first place.

      Alcohol is the best example: back when I started drinking, a relatively small amount would wreck me – I remember embarrassing myself on single-digit amounts of drinks. I built up a tolerance by the time-tested method of frequently drinking too much. Since then, I’ve lost weight, and every time I drink enough to get drunk, it hits me harder earlier – but nowhere near as hard as a comparable amount of alcohol would have hit me when I was 18 – and if I keep drinking for a few days my tolerance comes back pretty quickly.

      • Adam says:

        I’d concur with tolerance coming back more quickly. Analogically, I’d say it’s similar to the way muscle memory works, i.e. someone who used to be an experienced weightlifter will get stronger faster after being detrained than someone who has never lifted at all.

    • Simon says:

      Cause and effect is hard to determine here. Do you have less receptors due to your long term speed habit or were you dosing because you began with a lower baseline? And there’s no ethical way to test this.

      • Dave Kinard says:

        This reminds me of something- the possibility that some receptor sub-types might upregulate, other might downregulate- and this could vary based on different levels of stimulation.

    • Gan says:

      Tolerance varies by chemical and obviously user. Tolerance breaks or “T-breaks” pretty standard among daily (marijuana) smokers, since after a few weeks effects tend to reset. Dissociatives like ketamine have pretty notorious tolerance builds — it happens quickly, and can last years or decades. A lot of ex-ravers from the 90s who abused K for a couple years have been trying to find new dissociative analogues that won’t carry their tolerance over, because even 20 years out they either require heroic-sized doses to feel effects, or report only feeling a vague sense of haziness/fog regardless of dose. In other words, the magic is lost.

      I’ve heard of this happening long-term with MDMA, though I’d imagine the brain damage through excitotoxicity is way higher than that of ketamine. It’s also well-established drug culture canon that the first real opiate high can never be matched; that there’s something so uniquely magical about the effects of the first time that it’s impossible to replicate. Sometimes this is chocked up to chemicals but a psychological effect seems a more likely explanation.

      • Dave Kinard says:

        “Sometimes this is chocked up to chemicals but a psychological effect seems a more likely explanation.”

        All psychological effects are the results of chemical interactions- just sometimes very complex ones.

  72. Jadagul says:

    A friend who’s studying neuropsych stuff sends along this reference on naltrexone:

    The mu-opioid receptor (OPRM1) is the primary binding site of action for many opioid drugs and for binding of beta-endorphins. One of the effects of opiate and alcohol use is to increase release of beta-endorphins, which subsequently increases release of dopamine and stimulates cravings. Naltrexone is an opioid antagonist used to treat abuse of opiates, alcohol, and other substances. Naltrexone binds to OPRM1, preventing beta-endorphin binding and subsequently reducing the craving for substances of abuse.(1)

    She also suggests that people actually do become chemically adjusted to xanax and adderall, and most of the persistent effects of those are placebo. I’m more skeptical of that claim and she didn’t have references for me, though.

    • Wilj says:

      I actually tested that (indirectly) with placebo (flour) pills and self-pressed alprazolam powder pills. Inspired by Gwen’s efforts, I wanted to see if Xanax actually helped anxiety or just made me think it did due to sedation. I had been on alprazolam for about two years on a consistent dose of 2mg per day. I did 30 trials (1/day for a month) and was able to tell almost 100% of the time (only one error near the end).

      This will not be surprising to anyone who has used benzos long-term, I think. The longest I’ve taken amphetamine is about a month at a time, so I’m not sure about that, but the conventional wisdom is certainly that it keeps working.

      Note: in the two years of using alprazolam, I usually skipped two days at the end of the month. Maybe it would be different with no breaks at all. Two days isn’t long to reset everything, though…

  73. Ezra says:

    If you ever figure out anything more like this, I hope it gets posted on the blog. Thanks for another article, really good stuff.

  74. Anonymous says:

    Some situations that would work differently, maybe? (Take with huge grain of salt)

    – A patient is depressed because he has a completely shitty life, you give him drugs that enable him to go back to that shitty life, which perhaps keeps deteriorating.

    – A patient is depressed because he has a completely shitty life, you give him drugs that provide him energy to fix or escape his shitty life.

    – A patient is depressed because he beat his head or has some kind of trauma (Calibrated to his genetics, whatever), you give him drugs…

    I think focusing on eliminating the illness/reaction instead of the causes behind it works great in some cases and horribly in others.

    • Jill says:

      Good points. All these people get lumped into “depressed people” and maybe all the drugs as “anti-depressants” but maybe there are large differences among the people and the drugs and the reactions of particular people’s bodies to particular drugs.

      • Dave Kinard says:

        Absolutely. The “I just lost my job and my wife left me” depression is to the “20 years of choking on the abyss to the point where being sad over a death is better because it at least i feel something that has some tangible connection to the world” as a Human is to a Jack Russell Terrier. And it’s not even a linear scale, dig.

  75. Theory: the 5-HT2A receptor’s only purpose is to receive exogenous chemicals.

    • Dave Kinard says:

      You win the Big Pharma Science Prize. Free pens and hats for you. And you can star in a commercial with cartoon sadness clouds blocking cartoon serotonergic dendrites. Then the company logo makes them go away, and you’ll be playing tennis and smiling at children.

  76. Garrett says:

    Anecdote time:
    I’m on (among other things) Adderall. The first time I took it my reaction was “so that’s why this is a Schedule II drug”. Fortunately, I have a “low potential for addiction”. Taking as prescribed, the warm, snuggly feeling from the drug ceased to occur at all after about 3 months. However, the attention-management aspects still seem to be effective even years later.

    • Deiseach says:

      I think psychological addiction is also a factor, as distinct from physiological addiction, and this further muddies the waters.

      Re: Xanax, back when I was having anxiety attacks, my GP offered to prescribe these to me and I asked for the lowest dose for the shortest time (because I have a paternal family history where I see family members getting addicted to psychiatric meds).

      It worked marvellously, mostly by knocking me out (I’d keel over with drowsiness and have to go to bed, but compared with the effects of the anxiety, being a zombie was heavenly). Once I finished the ten tablets, though, I didn’t go back for more (even though my doctor was willing to renew the prescription) because I could tell I would become dependent on them. Maybe not physically but certainly I’d be using them as a crutch (getting anxious about getting anxious, so taking a tablet to stave off a possible attack in the kind of vicious circle which means you end up constantly pill-popping in case you get a fit of anxiety about getting a fit of anxiety about getting a fit of anxiety).

      • Passing By And Thought I'd Drop In says:

        I’ve been very successfully using a bottle of xanax as an anti-anxiety medication for 3 years now. I was having anxiety about the consequences of uncontrolled anxiety; the peace of mind in knowing that if things get bad I can take a pill has been enough to keep me from needing to take pills.

        • Deiseach says:

          That’s the reassurance of having it to hand, and certainly it helped me weather minor bouts by knowing if I really needed it, it was there.

          But I had to be strict with myself and not take the dose ‘just because’ if I was feeling a minor pang, and that’s the danger for some people: it relieves the attack and so when you feel a minor pang, you take one ‘just in case’ the minor pang turns out to be a major attack.

          Then you take one whether or not you’re feeling a pang, ‘just in case’. Then you’re anxious about not having enough, so you build up a stash. Then you take one before you go out the door. Then you can’t go anywhere without the pill bottle on you. Then you’re taking multiple doses a day to keep level.

          This is the kind of behaviour I saw in a close family member (not Xanax, Valium) and one I was afraid of developing myself.

  77. HeelBearCub says:

    Shits complex, yo.

    Seriously, why do people (especially very smart people) think that pumping similar inputs into different opaque boxes with highly uncertain starting conditions should produce consistent outputs?

    • Nicholas says:

      A lack of explicit systems theory in post-secondary education.

    • Anonymous says:

      A propensity for learned thought structuring of the kind that makes people see common sense as pseudoscience or “hippie bullshit”, overspecialization and tunnel vision, total rejection of subjectivity, etc.

      They like to pretend people can act or justify actions without aesthetic motives and considerations, which is a self-serving cognitive trick. Some even believe this is valuable. Some are so deluded they see different things as the same thing, or claim the difference is “illusory” or not relevant and should be ignored.

      Zombies, basically.

    • Zippy says:

      “Complexity” is not a real answer, and giving up is unlikely to further the medical field.

      • HeelBearCub says:

        Complexity isn’t an answer for why something happens. Of course, in this case, neither is “the psych teacher flipped the neurons before class”.

        But complex, dynamic systems can give different outputs under very similar conditions, so if we already know that a system is complex and dynamic, we shouldn’t be surprised when we find examples of this. Especially, especially, when we are dealing with not the same system but multiple different complex and dynamic systems.

        Also, that post is nice crystallization of EYs tendency to “storify” his lessons, and how that can fall flat. First off, many people would answer “because the plate was turned around” and the fact that they don’t is because, like a good Bayesian, they are using their priors. Their priors on “my teacher is trying to make us look foolish” is very low, and their prior on “the easy and obvious answer for these kinds of demonstrations is wrong” is quite high.

        Also, I said nothing about giving up.

        • PGD says:

          LOL, great comment HeelBearCub. Particularly the defense of the poor students in the example.

          In psychology we are dealing with multiple complex dynamic systems interacting — the body (non-brain endocrine system, etc.), the brain, the social environment. The distance you have to go before science really truly lifts you out of the need to consult common sense, rules of thumb, and trial and error is very considerable and I don’t think we’re anywhere near there. My deep-dive experience with working with highly qualified doctors to figure out the causes, predictability, and benefit-maximizing course of treatment for very infrequent seizures was illuminating in this regard. Big system failures like seizures seem like they would be *relatively* straightforward and biologically predictable compared to mood disorders like depression, but there were still absolutely enormous uncertainties about basic matters like causes, recurrence, mechanisms of operations for drugs, the net benefits over time of drug treatment, etc.

          To their credit, the doctors were pretty honest about this when questioned in a reasonable way (once moved off the checklists).

        • Deiseach says:

          Their priors on “my teacher is trying to make us look foolish” is very low, and their prior on “the easy and obvious answer for these kinds of demonstrations is wrong” is quite high.

          Presumably, answering “Because this is a trick question and you’re an asshole trying to make us look like idiots”, even if it occurs to the students, is unlikely to happen because they know pissing off the person grading your results is a bad idea.

          And really, an instructor pulling those kinds of stunts is not teaching their students “examine your prejudices” or “whenever you have eliminated the impossible, whatever remains- no matter how improbable – must be true”, they’re teaching them “never be first to answer because whatever you say is likely to be wrong as you’re being set up to fail, and sounding like an idiot will get you scolded by the teacher for being a conventionally-minded idiot who can’t think for themselves”.

          • Vaniver says:

            Whenever I have given the correct answer to a question like this, teachers have been impressed. I expect there are some people out there doing it for the dominance, but I doubt that’s the motivation for the median teacher doing these sorts of questions.

          • Lumifer says:

            I read the point of this story as a meta-lesson: don’t trust the default assumptions built into the situation. It has nothing to do with being Bayesian, it has to do with thinking outside the box.

        • Alex says:

          Thank you!

          Some observations:

          a) We witnessed the advent of a new literary genre called “The Sequences” and it is very well accepted around here to make statements of the form “X because of buzzword from The Sequences”. Not wanting to offend anyone but that is exactly the thing Yudkowsky criticises.

          b) The morale of Yudkowsky’s story hinges on his interpretation that these poor fools were thinking they were conducting science. The story as told does in no way support that interpretation.

          c) Sherlock Holmes would have found the correct solution. The difference between Sherlock Holmes and mere mortals is that Sherlock Holmes can search the whole infinite space of every possible hypothesis and rule out every hypothesis but one (he claims to have that ability almost verbatim) whereas mere mortals are biased when they generate hypotheses in the first place because otherwise they would not function as human beings. No amount of so called rationality will change that. The brain can do many things but it cannot consider literally every hypothesis, Holmes style. The anecdote is stragenly at odds with Yudkowsky’s criticism of Holmes as a literary figure.

          d) That being said, the most charitable reading, that I can come up with, is that Yudkowsky thinks the correct answer would have been: “well this fundamentally contradicts all beliefs I ever had about reality, and frankly, I do no have enough data to make something of it”. The difference between the students and Yudkowsky’s “true master” is not only, as Yudkowsky suggests, one of methodology, but first and foremost the fact the the physicist can be reasonably sure that he would know if such a phenomenon was possible as a property of the material or something like that, and the student cannot be so sure.

          e) The first lesson of rationality ought to be “never enter a mindset in which you think it wise to sneer at the students in this story. You are them and you will be them forever, because you are human”. I have the strong feeling that Yudkowsky is not the right teacher for that lesson.

          • Anonymous says:

            We witnessed the advent of a new literary genre called “The Sequences”

            GED was the original “sequences.”

          • Alethenous says:

            >You are them and you will be them forever, because you are human.

            I’m fairly sure Eliezer is working on that particular problem.

          • Deiseach says:

            The moral of that story could be if, say, the Curiosity rover finds a rock in the Martian crater that is cooler on the surface exposed to the sun, we should explain it as “Aliens flipped the rock before it got there” 🙂

            “Maybe the measurement was done incorrectly?”

            “Nah, it was aliens, man.”

            “But it could be a unique type of material never before encountered?”

            “Flipped the rock over. Aliens. Totally did it.”

            “But okay, maybe the vibrations of Curiosity driving up moved the rock -”

            “ALIENS. FLIPPED. THE. ROCK. OVER. Stop looking for alternate explanations!”

          • Vaniver says:

            We witnessed the advent of a new literary genre called “The Sequences” and it is very well accepted around here to make statements of the form “X because of buzzword from The Sequences”. Not wanting to offend anyone but that is exactly the thing Yudkowsky criticises.

            Obviously, saying “X is true because Yudkowsky says” is missing the point of the sequences. But being able to say “X is an example of this cluster pointed at by Yudkowsky” is the primary benefit of being in a community with sufficient background familiarity of The Sequences.

        • John Faben says:

          the fact that they don’t is because, like a good Bayesian, they are using their priors

          Actually, the fact that they didn’t is because *it’s a joke, and the events in that story have never actually happened to any teacher ever* – there’s even a reference for the story in the ebook version of the sequences, and it points to a page of science jokes.

          Sorry for the little rant – it has just always really bugged me that Eliezer presents this story as true, and then keeps discussing it in various future posts when it’s just really obviously not what would happen in a real classroom. Eliezer does mention this in a comment, but still, talk about Generalising from Fictional Evidence.

          • Deiseach says:

            But even as jokes these stories annoy me because, as you point out, no sensible teacher anywhere ever tried this kind of thing (and the teachers that would are the ones students complain about to one another as that person who makes things harder for you by messing you around).

          • HeelBearCub says:

            @John Faben:
            I never, ever though that story was a true story. Just like the stories of EYs that occur in the future, I pretty much assume every account of human interaction in the sequences is made up.

            But it does annoy me that this (like many of the others) is supposed to a good story to illustrate proper Bayesian reasoning. Even taken as a fictional story it falls flat on EYs own measurement scale.

          • FullMeta_Rationalist says:

            I know a friend with a similar story. Let’s call him John.

            Allegedly, his teacher (apropos of nothing) chalked “Why?” on the blackboard, then asked the class to write a response. While his classmates wrote florid essays on etiology, John simply wrote “because”. Only John received credit.

          • Douglas Knight says:

            I knew people in a physics lab class where the staff came in after hours and recalibrated everyone’s equipment, so that the results from the class were consistent with each other, but not with the published numbers.

      • Dave Kinard says:

        Pointing out the premise is wrong, and is a simplification of a much more complex process, IS an answer for why “According to Premise X, we should see Y, but we see sometimes Y, Sometimes Z, Sometimes W, etc”

    • Murphy says:

      because most of the time it does produce reasonably similar outputs?

      For example pumping opiates into people fairly consistently deadens pain. It doesn’t work very well for some people, sometimes that 1/100 horse comes in but most of the time it’s a safe bet.

      The cases where you don’t get consistent outputs are interesting because they can provide a lot of useful information about the systems in question.

      just shouting “it’s complex! I give up!” is probably the worst possible thing they could do. Might as well just start praying to lightening struck tree stumps and hoping for the best if you’re going to do that at the drop of a hat.

      • HeelBearCub says:

        I said nothing about about giving up. My point was to express mild frustration of the tendency to expect biological systems to be neat and tidy.

      • Deiseach says:

        The interesting question here is why tolerance isn’t more widespread. How is it that most people can bump along happily for years on a set dosage of, say, blood pressure medication and it reliably works long-term? Sure, maybe they need the dose increased a bit over time, but why don’t we see people coming in after six months saying “Doc, it’s not working any more” the way we might with anti-depressants?

        • Dave Kinard says:

          Probably the nature of the brain, which produces much more variable responses to changing circumstances then the circulatory system, which, though it has different speed settings, basically just has to do the same thing over and over again.

    • PGD says:

      Well, something like that assumption is necessary to support wealth / power / influence for a lot of people who make scientifically derived products. ‘Try this drug, it can be helpful in some cases but it might not in others and can be actively dangerous in still others, so be careful’ is not going to get you billions in sales. Real respect for complex systems theory when it comes to social and psychological theory loses you the prestige and influence you get from pretending your results are as replicable and predictable as physics or chemistry.

    • Lumifer says:

      why do people (especially very smart people) think that pumping similar inputs into different opaque boxes with highly uncertain starting conditions should produce consistent outputs?

      Physics envy.

    • JayT says:

      Seriously, why do people (especially very smart people) think that pumping similar inputs into different opaque boxes with highly uncertain starting conditions should produce consistent outputs?

      Because they don’t have a better approach? I mean, if one thing works for a larger number of people than any other treatment, why wouldn’t you start with that? Then, if the person is atypical, then you move on to a different approach. It seems very reasonable to me.

      • HeelBearCub says:

        There is a difference between “I am going to try the thing that works 80% of the time”, on the one hand, and then being surprised when 1 in 5 of your patients don’t respond to the medication, on the other hand.

        Scott saying that it’s really “weird” that a medicine can have an effect, no effect or the opposite effect is like expressing surprise that 1 in 5 patients didn’t respond.

        Now I get that sometimes we all go “hey look at this counter-intuitive result isn’t that weird?” and we don’t mean weird, I can’t believe it, but weird, isn’t this interesting and cool.

        But that isn’t what I am reading from Scott here. I am reading “why the heck would nature design a system this way?”

        And my response is that we should expect these things. We should expect to encounter them all the time. And we should expect more and more of the problems we are trying to solve in medicine, biology, etc. to be precisely these kinds of problems. Because the simple ones were the easiest to solve.

        A former boss and colleague of mine likes to say “it’s good to have hard problems to solve” (because that is where the profit is). Now, when you are treating a patient it’s nice (for everyone especially the patient) to have an easy problems to solve, but still ….

    • Utopn Naxl says:

      Ya bru. Me inject da cyanide in da bub streem ta kill da da da fool. He go bye bye fast. Work uh on da everyone.

      Or, with plenty of chemicals, it does have consistent results for most people.

      Those amazing stories of variability of alcohol tend to go away in the lab when corrected for tolerance and body-size.

  78. Daniel Speyer says:


    Replacing receptors in far-flung dendrites is a lot of work: either mRNAs or proteins need to be transported for centimeters. Therefore you don’t want to be replacing them frequently, so there’s strong evolutionary pressure for those proteins to last a while once deployed. Let us assume evolution has solved this problem.

    Increasing the count means spinning up a bunch of expensive cellular machinery that normally isn’t there at all. Decreasing the count is even worse: it means making proteases. This isn’t your normal tweaks to an ongoing transcription rate.

    How might the cell avoid waste? Possibly by having an acceptable zone with rapid correction outside of it instead of a smoother optimizing feedback mechanism. A sharp zone boundary is unlikely, but requiring simultaneous attachments at multiple points lets it raise the correction level to a high power, which is similar. And the low rates become low probabilities once the concentrations get below one molecule/cell of an intermediate messenger.

    Does this explain some of our observations? It explains why a high dose has a greater tolerance risk than a chronic low dose. It explains why when a compensation mechanism is failing, making the problem worse can help. If we assume time delays (and when diffusing chemicals are carrying signals across centimeters, that’s a given) it explains why tolerance can be greater than total. It kind of explains why someone can be ok for a while and then acquire tolerance suddenly: if they were near the cutoff and random noise bumped them over it.

    It doesn’t explain why we see some dopaminergic tolerance effects and not others. Maybe different mechanisms in different cell types? Maybe different de facto thresholds for the same mechanism in different shape cells with different diffusion?

    It also doesn’t explain different people having different reactions, but that’s just not very surprising to begin with.

    Apart from finding the chemical mechanisms, I’m not sure what would be confirmatory evidence for this.

    • Daniel Speyer says:

      I know no one has reason to believe this, but I promise it’s true:

      I started composing my comment before Adam posted about his opiate experiences. As I wrote the last paragraph, I thought “One sign would be if tolerances happened faster in smaller neurons. And the biggest neurons are in the peripheral nervous system. So I predict less tolerance and more weirdness in pain than in psychiatry.” And this is exactly what Adam reports: with an n=1 controlled experiment.

      I didn’t post that because I imagined not seeing this and found I wasn’t updating. Too many ways for cellular machinery that’s needed one place to be reused in others.

      So call it half of a successful prediction.

    • Daniel Speyer says:

      Further thought: could bipolar disorder be a breakdown in this?

      Having a narrow target window is good because it keeps your mood on an evener, better-calibrated keel. Having fast correction is good because it keeps you out of the trouble zones. But having both at once means frequently overshooting from one side to the other.

      Though, if so, why does the entire brain go at once, instead of each cell in its own unsynchronized pattern?

      Prediction: bipolar should be more common in people of mixed ancestry.

    • Cadie says:

      Interesting. I’ve taken Adderall at low doses for about 5 years now. I got used to a few of the effects quickly – the first few days I couldn’t sleep well and after that I could as long as I didn’t take it too late in the day, and it took almost two months for my appetite to return to normal. But I STILL find it makes a dramatic difference in my concentation ability and memory, even after five years at 10-20mg/day. And if I skip a dose, I don’t have noticeable withdrawals, I simply feel like my scatterbrained and stressed-out self. Maybe it IS a little worse than before medicating – my memory for precisely how I felt on some random day c. 2010 isn’t very good – but if so, it’s not enough to be obvious.

      Maybe the low dosage is just enough to bring some neurotransmitters into a normal/healthy range and there’s not enough medication to spill over and have strong unwanted effects.

  79. Mary says:

    “Everyone knows about tolerance. The first time you take heroin, you get really high. The second time you take heroin, you get slightly less high. The nth time you take heroin, you barely feel good at all – ”

    Pedant hat on.

    Only if you take it often enough. There have been many recorded cases where people took opiates for years without this effect by the simple expedient of taking them only once a week. (Reference Romancing the Opiates)

    • Utopn Naxl says:

      >There have been many recorded cases where people took opiates for years without this effect by the simple expedient of taking them only once a week.

      That point needs to be emphasized more about these drugs. Everyone likes discouraging that statement as “responsible” adults, though.

    • Dave Kinard says:

      Also- and this is really weird- from what i’ve heard and understood, most people don’t love heroin the first time- they just get nauseated. It apparently takes at least some time to get the euphoria.

  80. Adam says:

    I’ve been using narcotic painkillers pretty consistently since about late March, at least every night until two and a half weeks ago when I had surgery, and then every four hours since then (as well as on and off as flareups come for the last four years). I do notice euphoria-inducement tolerance. If I stop for a few days and take one again, it won’t just kill the pain. It will make me feel like I’ve melted and gone to heaven, and that will go away after a second or third dose, so very quickly. But the painkilling effect is pretty consistent. In fact, it’s barely perceptible. It gets to the point where I feel like I’m fine now and will stop taking them, so I stop, then nope, pain is back. If that is happening in two months, I’ll probably start to worry, but two and a half weeks post-back surgery seems like it’s still reasonable. The incision site is definitely inflamed and I was given steroids for that, so I’m reasonably certain I’m not just imagining this. I’m also reasonably certain I don’t seem susceptible to painkilling tolerance and have never tried to up the dose and am not worried about getting addicted, as I’ve been perfectly able to stop so many times before when the pain really did go away for a long time. On the other hand, I’m no longer married to my first wife because of how thoroughly and devastatingly it ruined her to become addicted to exactly the same medication after hip surgery in 2001. Like she was just straight up buying it on the street and pill-popping for years. But, now that I have some personal experience and understanding of the drug, I suspect her hip problem was long gone and she was taking it for the euphoria.

    • Adam says:

      I feel like I should add your post about chronic pain being psychosomatic psyched me the fucked out and had me filled with self-doubt for weeks. You’re right that MRIs suck and can’t possibly show everything that is wrong, especially since it’s often specific positions inducing the pain and MRIs only take place in optimally comfortable positions you are capable of holding steady for 30 minutes.

      I went through with my surgery because I trusted the judgment of the surgeon who had seen thousands of people like me, and when he opened me up, he told my wife I had as much arthritis in there as he’d ever seen in someone my age and I’d very likely need a disc replacement eventually. That felt validating. They shaved down two vertebrae and two discs and now it’s just waiting game to see how much this helps when it heals.

    • Ray System Pathee says:

      I’ve heard a lot of people describe the euphoric effects of opiates using words like “melted” and “heaven.” Can you be more specific or provide more detail? Maybe compare it to something, even a scaled-down something, that a non-opiate user might be able to relate to?

      • Adam says:

        The melting thing is about external sensation dulling. It feels like the outside world is just melting away.

        Have you ever experienced a state of reduced mental capacity from sleep deprivation, not like the level where you start going insane, but just a few hours past when you would normally fall asleep, and everything starts to seem funny, you can’t quite put together a coherent sentence, you’re not completely certain you’re not dreaming? It’s fairly similar to that.

      • brungl says:

        If an orgasm is a 10 on the euphoria scale, an average opiate (in a recreational dose taken orally, which is all I have experience with) is about an 8. Though it lasts much longer, obviously. As the effects come on, it gradually becomes harder to focus on anything except the pleasure, and what thoughts you have tend to become more abstract and dreamlike. The word “melted” in this context is often referring to the feeling of your troubles/concerns slowly dissipating.

        • Scott Alexander says:

          Hm…this made something click for me that’s probably going to make me sound really stupid..I’m asexual, I can’t orgasm when having sex, but I can sometimes make myself orgasm with the right stimulation. It feels relaxing and pleasant, but I don’t think I would describe it as “euphoric”. I’m guessing – and I should have figured this out a long time ago – that other people have a really different experience?

          • ilkarnal says:

            For me it’s a local, intense, pulsing burst of pleasure that lasts a couple of seconds. I wouldn’t describe it as ‘euphoric’ – that seems to imply something too holistic. Definitely wouldn’t call it ‘relaxing’ either.

          • Murphy says:

            I’m not sure orgasms make a good baseline since they vary so massively.

            5 minutes masturbating orgasm vs long sex session with person of your dreams is the difference between “that was satisfying” and losing the ability to stand for a few minutes.

          • brungl says:

            That’s interesting! I’d be curious to know which physical sensations (if any) you’d describe as “euphoric” if orgasms don’t make the cut.

          • K says:

            ” It feels relaxing and pleasant, but I don’t think I would describe it as “euphoric”.”

            Reminds me of Oliver Sacks’ description of his first orgasm in a swimming pool, IIRC. (In the book “Uncle Tungsten”) I thought that was odd, since I’m in the euphoric category myself – but apparently, people differ here as in many other things, and it is all too easy to generalize from one’s own experiences.

          • Rachelpalmer says:

            I’ve mostly spoken to other women about this – as far as I can tell there are vast differences in the way (non asexual) women experience orgasms – some seem to find them far more pleasurable than others. I’m guessing it varies a lot for men too.

          • Cadie says:

            FWIW, I don’t think I’ve ever had a euphoric experience – and I HAVE tried opiates and other medications that generally would trigger it. Oxymorphone felt like sort of like a benzo, but a little stronger on the anxiolytic part and a little weaker on the sleepiness part (benzos make me really sleepy if they do anything at all). Nice to have anxiety going away but it didn’t make me feel GOOD, just not-bad-anymore. Hydrocodone feels like combining a stiff dose of Advil and some caffeine with Benadryl – migraine significantly weakened, a little less anxious and a little sleepy but not too much. Codeine feels like Skittles (the actual candy) except the one time I took it with a muscle relaxer AND a prescription anxiolytic and then it got rid of my insomnia quickly and and made my broken ribs hurt less without changing my mood. At least not changing my mood beyond what you’d expect from a reduction in rib pain.

            I’ve often thought I’m simply incapable of euphoria/physical pleasure. I find some things mentally fun or interesting – I prefer playing a game to staring at a wall for no reason. But it took me into my 30s before I figured out that “comfort” probably means something stronger than “hard, lumpy chairs hurt your butt and soft chairs don’t so pick the soft chair, it won’t be a literal pain in the ass” and the pleasure from sex is supposed to be more than being proud of oneself making one’s partner happy. Even cocaine felt like a smoother version of espresso: energy and wakefulness, not much else. It’s frustrating to know that I’m missing something most people experience and really enjoy and it probably can’t be fixed with medication because if it could be, something out of the two dozen or so medications I’ve taken over the years would have at least worked temporarily.

        • Anon for the obv reason says:

          I’d have put it the other way for cocaine, which I had far more experience with than opiates (in younger days – long since stopped). A strong orgasm maybe 6-8, decent line of cocaine 9-10, cocaine + orgasm 11. As Whoopi Goldberg said, it was like being inside of joy. But very not worth it past the first few experiences – it quickly goes downhill to the point where you’re doing one line to feel great for 5 minutes then staying up for 48 hours finishing two more 8-balls just to avoid the awful come down (adjusting for different response curves as described in the OP).

      • suntzuanime says:

        I was on Vicodin for a couple weeks for a nasty tooth infection and I never felt any euphoria at all, it just made me sleepy and reduced my pain. I felt kind of cheated, although killing the pain was nice I *guess*.

        • Gbdub says:

          Yeah same here, It did nothing for me really but help me sleep. The actual pain reduction didn’t seem much better than acetaminophen (which Vicodin contains) or ibuprofen, but I cared about it less.

          I guess I can see where you’d get the “melting away” feeling, as it was kind of a dissociative / fuzzy feeling, but I found that more unpleasant than euphoric. Also it gave me wicked hangovers.

          When I had knee surgery I stopped taking it during the day almost immediately, took it at night for about a week to help sleep through nagging pain, but I can’t imagine using the stuff recreationally.

        • The Nybbler says:

          Same with me on Percocet. And not even enough painkilling to produce the feeling of “sudden cessation of pain”. Not sure if it’s me or just the dosage; oxycodone abusers take a lot more than 5-10mg at a time.

        • Deiseach says:

          Took a paracetamol/codeine combination painkiller for really bad muscle pain and I got the “whoo – floaty!” reaction which was very pleasant and unexpected, but I can’t say it made me melt or feel very strongly euphoric. I think I built up a bit of tolerance as well as I was taking them at intervals over a long period, and the ‘floaty’ high faded quite a bit (still felt it a little but not as strongly as the first couple of times).

          So I can see how someone would want to continue having that feeling if it were very strong for them and it lasted a long time before tolerance set in.

          • anon says:

            That sounds similar to my own (single) experience with opiates, which was also Tylenol with codeine (after a dental operation). Floaty but not really euphoric. I enjoyed it, but I only took the pills for a few days and experienced no tolerance.

        • Nornagest says:

          Same for me on oxycodone. It didn’t even kill the pain all that well.

      • Wilj says:

        I always describe it like: imagine your immediate goals are all suddenly accomplished or about to be, and you’re in a hot tub after eating a delicious meal, and you’re just beginning your favorite activity in the world and it seems even more interesting than usual.

        That sense of “everything is perfect, everything is possible, I want to do everything, and I feel great physically too” is why I became a little too into opioids for a while. They helped my depression and motivation; I never had any negative effects from them, both in pharmacological terms and in general,* but I don’t recommend them because I do see people get into trouble.

        *Well, aside from taking my spare cash.

        • Ray System Pathee says:

          That description perfectly matches my typical experience with marijuana (especially when smoked alone), which in turn makes me more confused about what the opiate experience is like. I have to assume they’re very different.

          • Wilj says:

            Either you get amazingly intense effects from cannabis, or I have not emphasized the intensity of opioid euphoria enough!

            Cannabis is another of my favorite experiences, and it’s not entirely dissimilar, so I think I can see what you’re saying; but it’s definitely not exactly the same — for me, anyway; maybe it really is the same for you!

            It’s less intense, as stated, and also much less emotional… if that’s the right word. Yes, things are more interesting with cannabis, but it’s because I’m more easily amused… not so much more motivated, but less easily bored. With opioids, it’s that I’m suffused with energy and everything is pleasing. Like the difference between making a good game tolerable, vs every game your favourite.

            Similarly, regarding physical pleasure, cannabis does make me feel good, but in a sort of “insulated” or muted way, like crawling under warm covers. Opioids make me feel the eye-rolling-back “aaaah” of a great massage, say.

    • Max says:

      My only experience with opiates is getting intravenous Dilaudid in a hospital. I didn’t feel any euphoria at all. It just made me feel closer to normal. But I was in extreme pain before the shots.

      • Adam says:

        I had the self-administered Dilaudid drip in the hospital, too, and definitely don’t recall any euphoria, but it wasn’t like I was starting from any normal baseline. I’d been taking narcotics for months anyway and anesthesia was still wearing off. I barely even remember any of this. It’s almost like I just lost a week of my life, but my wife keeps telling me hospital stories and sometimes pieces will come back when she reminds me.

  81. Jill says:

    There needs to be more research on cannabis, illegal drugs, and natural remedies. Some of these– although probably not most– are going to be found to work to cure various illnesses.

    A lot of people are claiming that cannabis cured them of various forms of cancer, so that definitely needs to be researched. Maybe it’s not true. But if it is true, for some kind(s) of cancer, it sure is a lot more pleasant a treatment, with fewer side effects, than chemo or radiation or surgery.

    • Enkidum says:

      Disagree. It is generally good to be *extremely* skeptical of any anecdotes about treatments for anything, particularly ones made by people with a vested interest in them succeeding. In fact, I think our default position should be to assume that it’s all garbage unless given very strong evidence to the contrary. Basically, I’m claiming that Sagan’s dictum of “extraordinary claims require extraordinary evidence” should apply to anything anyone has ever said about medicine. Fortunately, we have a lot of extraordinary evidence out there. We have, by the standards of empirical research, unbelievably good evidence that washing your hands prior to surgery helps not kill patients, or that willow bark derivatives are useful for alleviating various kinds of pain, etc.

      There is absolutely nothing in what we know about the mechanics of cannabis that would relate to curing cancer. And we know a fuck of a lot about cancer, at the very least. Without a promising theoretical reason to consider it, there’s nothing indicating that cannabis would be a better research topic than, say, windshield washer fluid, magnets, pine needles, or cognitive-behavioural therapy. And “a lot of people are claiming that cannabis cured them of various forms of cancer” is not a good theoretical (or empirical) reason.

      Also, for what it’s worth, I know a fair number of kooks and occasionally read their websites, and I’ve never seen anyone make the claim you’re giving. Lots of people say that it helps with the nausea and pain, and that it helps combat other unpleasant side effects of the cancer and chemo, but I’ve never heard of anyone touting it as a cure.

      But if they are, who cares? I’m out of date, but the hot new fad for curing cancer was once shark cartilage, which a lot of scumbags used to sell a lot of books (and presumably supplements) to desperate people. Some proportion of those people had cancer that went into remission. Who cares? This is not how research should be instigated.

    • Pete says:

      I don’t recall seeing *any* claims of cannabis as a cure for “various forms of cancer”, can you be more specific?

      Cannabis does have a potential use in cancer treatment, but it’s to *support* chemotherapy, not replace it – it can mitigate chemo side effects, but isn’t an active cure by itself.

      • fubarobfusco says:

        There seems to be some research on cannabinoids inhibiting tumor formation. See, for instance, this review.

      • Glen Raphael says:

        I don’t recall seeing *any* claims of cannabis as a cure for “various forms of cancer”, can you be more specific?

        The most common use for marijuana in the context of cancer treatment is alongside chemotherapy. Pot increases appetite (aka “the munchies”) and suppresses nausea. People who are nauseous due to chemo can’t reliably keep down pills; smoking pot is a useful way to self-dose with a drug that can help them eat and avoid “wasting syndrome”.

        Additionally, there are at least a few cases where people who smoked pot to increase appetite or reduce pain found their cancer situation improved and credited the pot. The highest-profile case that comes to mind is Steve Kubby.

  82. Jill says:

    Everybody who does research has to write up a section of their report that explains why the result happened. But I wish it were an easy thing for researchers to just admit “I am clueless as to why it turned out this way.” Because sometimes that’s the way it is.

    If something works to alleviate or cure physical or mental illness, that’s great. But to pretend you immediately know why it did what it did, is silly.

  83. Jill says:

    We don’t all look alike on the outside. Why should our bodies look or function exactly alike on the inside, such that they would all metabolize drugs the same way? I had a physician once who, when he prescribed medicines, told people that if the standard dose felt like too much, that he would work with them to see if there was a better dose for them. Some people ended up only responding well if they took more than the typical dose. Other people ended up shaving little bits off of a tablet with a razor blade and reported they were getting the full effect of the drug that way. Saves them money at the pharmacy too.

    I have a friend who has MS, in remission. She works full time as a school teacher, has a 2 hour commute per day, and walks 9 miles a day now, with no problem. When her MS was active, and she could hardly move, she was taking meds in IV form, called avenex, dripped into her once a week, which worked well and made her body function normally after a day or 2 of side effects. She hated the severe painful side effects, so she found a doctor who would work with her on decreasing the meds. The doctor didn’t want to take too much risk, so she decreased it one drop per week. After 3 years, she was on a drop per week. She was still feeling healthy, but still experiencing the full side effects, so her doctor said “Okay, let’s try you off of it entirely.” It’s been in remission ever since, and that’s been 10 years or so.

    There ought to be more research on drug dosages, tolerance, and sensitization. And there needs to be not just average effects or lack thereof, but they need to look at what percentage of people experience the drug’s intended effects, and for how long, and also look at tolerance, or sensitization.

  84. Ray System Pathee says:

    I’ve thought about tolerance applying to lots of other things, not just drugs.

    For example, music. I will thumbs-down my favorite songs on Pandora just to preserve their freshness to my ears.

    One of the reasons I don’t use social media is because I know it is designed to produce small releases of dopamine in the user’s brain through many of its interactions. I am uncomfortable about the long-term effects this would have on me. (I also have many other reasons for not using social media, but this one was relevant).

    • Ray System Pathee says:

      Oh yeah, one more thing I’m always thinking about in terms of tolerance: my eye glasses.

      I know there have been several high profile cases of people claiming to be able to cure myopia with eye exercises and that it hasn’t ever worked. I believe it! It’s probably like trying to keep a bathtub from emptying by adding water into it with an eyedropper.

      But what about slowing the rate of decay? I’ve been wearing glasses since 2nd grade. In 5th grade I was introduced to this kooky Israeli woman who practiced Reiki and stuff like that, and she taught me these eye exercises that I did pretty regularly for 3 years. By 8th grade my eyes had only weakened one quarter of a point in whatever scale they use for eyeglass prescriptions, while my twin brother’s weakened by something like 1.5 points on that same scale over that same time period. He hadn’t been taught those exercises.

      Glasses are a crutch, and without them the muscles that squeeze the lenses in my eyes have to work a bit harder. Maybe even with hard work they can never get in good enough shape for my vision to return to 20/20, but I don’t see why working hard from time to time wouldn’t slow their rate of decay.

      • Guy says:

        I became nearsighted enough to need glasses when I was about 16 – at this point it was no longer feasible for me to read a blackboard from the back of the larger classrooms in my high school. However, I’ve noticed that I’m pretty good at figuring out what an initially unreadable bit of writing says, and that my eyes sometimes just seem to take an inordinately long time to focus properly. I put this down to my visual processing being unusually good at error correction, compensating for unusually weak eyes. If I wore glasses earlier and/or more often, I would never have gotten the error correction practice. Could this improved error correction mechanism explain the effect you’re experiencing?

        • Ray System Pathee says:

          That almost perfectly describes one of my eye exercises. I’d bet that giving my visual processing center some hard work to do is indeed part of what I’m exercising, but it’s also definitely physical in my eye sockets as well. I can feel the muscles there straining and relaxing, and I can feel a “burn” just like if I was doing squats. It’s unmistakable.

      • jes5199 says:

        when I got LASIK, I asked the doctor if my vision would still get nearsighted at the same rate it had been all my life (something like 0.25 diopters every two years). She said no – that *wearing glasses* makes your vision gradually get worse, but if your vision is clear without them it’s likely to remain stable. I don’t know if that’s literally true, but it fits my experience so far.

      • Alliteration says:

        Some studies seem to go against this idea.
        Undercorrection of myopia enhances rather than inhibits myopia progression.
        The progression of myopia from its onset at age 8-12 to adulthood and the influence of heredity and external factors on myopic progression. A 23-year follow-up study.
        (Though these studies were on children which may be different from adults.)

        BBC Future summary of these studies (which is the where I found these studies, so this could perhaps be a biased sample of the research if the BBC author was biased.)

  85. anonymous says:

    I’ve similarly heard mixed reports about piracetam – tolerance, no tolerance, and (I think) negative tolerance.

  86. Ray System Pathee says:

    OK, traffic/driving/car design research questions:

    1. From a geographic perspective, how do bumper sticker/window decal fads spread? I noticed there were way more of these when I moved from LA to San Diego. Then when I moved back to the Midwest, they were everywhere even though I didn’t remember seeing them before I left.

    2. Are angrier-looking cars driven more aggressively?

    3. Does having an angrier-looking car in your rear view mirror make you drive more defensively?

    4. Do more lesbians than straight women drive stick?

    5. Are manual transmission drivers better at driving? If so, then by what metrics? What about parking?

    6. If you have a long commute involving the highway or have coworkers who have them, you’re probably familiar with the act of waiting until rush-hour is over to go home, figuring you’ll get home at about the same time but avoid all the stop-n-go traffic. But rush-hour doesn’t just suddenly end, does it? So, is there a mathematical formula to figure out the ideal time to leave? How accurate does your timing tend to be?

    More as I think of them.

  87. Acedia says:

    Mildly relieved to see it acknowledged by a doctor that developing a tolerance to benzos in a matter of weeks is possible. It happened to me with Lorazepam, which worked wonderfully for my anxiety for two or three weeks and after that suddenly needed enormous doses to have any detectable effect (I chose to stop taking it at that point rather than ask for more, since I didn’t want to become dependent). My psych and GP insisted that I must have been imagining it because tolerance always takes multiple months to develop.

    • Jill says:

      Doctors are often unaware that not everyone will respond to a drug like the average person in some research study did. You’re not the average person in that research study. You’re you.

  88. Daniel says:

    Malcolm Gladwell wrote an essay containing the idea that the level of intoxication one experiences from alcohol is highly dependant on the cultural setting that one is consuming it in.

    Does anyone know anything more about this? I wouldn’t be surprised if inebriation is highly influenced by mental framing (ie if you think 3 drink will make you really drunk, it will), but since I know that alcohol poisoning is real thing, I don’t understand how this can work for high volumes of alcohol.

    I was recently with a group of girls from Finland who relayed to me that the girls in their friend group can drink between 18-26 ounces of vodka in one night. I don’t know a single girl in Canada or Israel (the two places I’ve lived) that can drink close to that (and this includes girls who partied a lot during college). If the Finnish girls were being honest, how much of this is due to genetics, and how much is due to culture?

    EDIT: here is the essay in question –

    • Good Burning Plastic says:

      Finland is a lot colder than Israel or the inhabited parts of Canada.

      • Jill says:

        Yes, perhaps climate has something to do with it.

      • Pete says:

        Not sure that is necessarily true. Edmonton hits -40C occasionally (I’ve experienced this) and regularly gets down to -30C. It may be colder in Finland, but I don’t believe it’s considerably colder.

        I mean, when you get down past -20, cold is cold.

        • Balor says:

          There’s a difference though between Canadians moving to there in the recent history, while we Finns have lived here for millenia.

          My personal theory is that we have been so poor as to not have yet selected against alcoholism to the same extent as people from richer/warmer areas – we didn’t have as much opportunity to indulge in it in the past, even if one was genetically predisposed to it.

          Or what exactly was your thought link between cold and alcohol tolerance?

      • Lumifer says:

        Finland is a lot colder than Israel or the inhabited parts of Canada.

        Don’t think it’s true with respect to Canada (once you get away from the coasts).

        But in any case I think it might have to do with being in high latitudes more than with the cold. You’ve got to do something during the long dark winters.

    • Vladimir says:

      Is anyone surprised Malcolm Gladwell is giving cultural explanations for obviously biological effects? That was cheap but seriously, you’re better off reading Gladwell’s citations than his actual work.

      • PGD says:

        It’s foolish to try to create a hard-and-fast separation between culture and biology. Human beings are biologically designed to be sensitive to cultural cues. We cannot survive without effectively cooperating with other human beings, culture refers to the systems we set up for interaction / cooperation / communication with other human beings, so extreme biological sensitivity to cultural cues makes all kinds of sense. So there is nothing contradictory about ‘cultural explanations for biological effects’.

        • SolveIt says:

          There’s nothing inherently wrong with cultural explanations for biological effects, but Malcolm Gladwell is a man with a very big hammer, and it’s not clear he can distinguish nails from non-nails, so to speak.

        • Lumifer says:

          It’s foolish to try to create a hard-and-fast separation between culture and biology.

          I don’t think so — this is a very useful distinction. Of course humans biologically are social/cultural creatures, but culture varies much more than biology and changes much much faster, too.

      • Utopn Naxl says:

        You are better off just never reading Gladwell.

    • Ray System Pathee says:

      I’m reminded of how lots of soldiers who were prescribed opiates for pain in bygone wars (up through Vietnam, whose soldiers had the most famous relevant study) returned home and resumed their lives without addiction, while at the same time civilians experimenting with those same drugs recreationally became addicted very quickly.

      Setting and expectations do seem to have an impact on the effects of the drug. I guess this is probably even more pronounced when the drug in question is not legal and so the user doesn’t really know what dose he’s getting.

      • fubarobfusco says:

        Maybe this is just behaviorism. Random reinforcement schedules are more habit-forming than fixed ones. Someone who’s taking street heroin is getting “randomized” dosages; they may not even be getting the same chemical.

        • Ray System Pathee says:

          Yeah, that’s what I said:

          I guess this is probably even more pronounced when the drug in question is not legal and so the user doesn’t really know what dose he’s getting.

          This is also the reason slot machines and Facebook are addictive.

          • Johan says:

            I do software developing and testing for slot machines for a living, and I can tell you that knowing the intricacies of the math makes them really boring to play – I would never play these things on my leisure time (even if you had even return on the bets, which of course you don’t).

            I’m very confident I’ve been immunized to addiction to this, at least.

        • Titan Uranus says:

          If you’re going to analyze opiate addiction assuming that behaviorism can explain most of the causes, then doesn’t it make more sense to posit that the main difference is that the soldiers are lying in a hospital bed recovering from some grievous injury (thus bored and in pain), or using it to deal with chronic pain (probably doing fewer fun activities, so again, bored and in pain).
          While, by contrast, the recreational users are doing it explicitly for recreation, are not in pain, and presumably have a more pleasant experience overall.

          Basically, in one case opiates are associated with pain and boredom, while in the other they are associated with euphoria and presumably friends.

      • hypnosifl says:

        The rat park experiment is also evidence for the importance of setting (or overall lifestyle)–in brief, lab rats in small confined cages would tend to become addicted to drugs like cocaine and heroin when given a lever they could press to administer small doses to themselves, but rats in a large enriched environment with a lot of stuff to play with, and other rats to interact with, did not consume these drugs nearly as much when given the same opportunity.

        • Ray System Pathee says:


          It’s fascinating how little we understand about addiction even after 100+ years of scientific study.

        • Scott Alexander says:

          Rat Park mostly didn’t replicate and I wish people would stop citing it as a real thing.

          • Gardenofaleph says:

            So is the current rat addiction literature mostly consistent on rats self administering heroin/cocainelmethemphetamine over sugar water?

            I need to really dig into this stuff at some point.

          • Anon says:

            Can’t find a metanalysis on this so I did a little digging myself. I looked into this and found 6 similar studies to Rat Park:

            One which completely failed to replicate, and offers genetic differences between the groups to be the cause of the difference in results:

            A modified version of the original whose results challenged the conclusion of the original:

            These were the only specifically “failure to replicates” I could find. There are lot’s of science articles that say there has been a massive failure to replicate, but I have only found these two studies and the only study cited by any of the articles saying there hasn’t been any replication was the first one I posted (Most of them don’t cite anything).

            A version which uses nicotine instead of “harder” drugs like cocain and heroine and successfully replicates the findings in the original rat park:

            Three studies that successfully replicate rat park and try to find a neurological mechanism for the phenomenon:

            So “Rat Park hasn’t been replicated” or even “mostly didn’t replicate” seems to be false.

            Still the real issue is probably more nuanced than the original study’s conclusion made it out to be. I’m going to wait on a metanalysis before having a strong opinion on the issue.

          • PGD says:

            See anon’s comment above re replication. But there’s all kinds of evidence in ordinary human life for ‘rat park’ type conclusions. It wouldn’t make much sense to do therapy (as opposed just being a hard core biological psychiatrist who does nothing but prescribe drugs) unless you felt that environment affects the propensity for self-destructive and counterproductive behavior.

          • GregS says:

            Thanks to Anon and PGD for their comments on rat park. I was with Scott on this in that I didn’t know about the successful replications. The Wikipedia article on Rat Park still says the experiment failed to replicate (which I read recently and assumed was true). I guess someone should update that.

            I’ll second PGD’s comment. Does anyone think that environment *doesn’t* matter? That drug users don’t consider the alternatives available to them, the opportunity costs they are incurring, etc.? The lessons of the original Rat Park might or might not apply to rats, but they certainly apply to humans. Even addicts respond to incentives, alternatives, positive influences, etc. These animal studies are interesting, but of very limited value to understanding human addiction.

      • C says:

        > Setting and expectations do seem to have an impact on the effects of the drug.

        “Set and setting.”

      • Ruben says:

        Also, just more generally selection effects: people who are inclined to do drugs recreationally presumably get more out of it. Plus, they have access to more drugs at home, the veterans would have to procure them first.
        All in all, this is so horribly confounded, that we are probably better off studying moderators of response in RCTs, if we want to learn anything real.

      • Fazathra says:

        How much of this is because it’s much harder to stay addicted when your only supply is the army who probably don’t give it to obvious addicts? Also, the withdrawal effects may be masked by the general shittiness of being in a warzone, so they may not even realize they were addicted.

        • addict says:

          No no no no no.

          Haven’t you seen American Gangster?

          The soldiers were purchasing it in heroin brothels run by Vietnamese. It was excessively recreational.

      • dndnrsn says:

        On the other hand, people (military or otherwise) prescribed opiates for pain do get addicted in enough numbers for it to be a problem: I’m pretty sure “morphine addicted ex-soldier” was a trope once, and isn’t somebody getting prescribed Oxys for their back and getting addicted the classic story?

        I imagine that one reason people get addicted to recreational things is that they enjoy them enough to seek them out, and are more likely to up the dosage: compared to someone prescribed it for pain or whatever, someone doing a drug recreationally is practically trying to get addicted.

        • Ray System Pathee says:

          But see I wonder whether the “former legit medical user, now addict” trope can’t really get started until the legit medical users learn that there are people out there using the same drugs recreationally.

    • Loki says:

      I definitely read something about blue-eyed people (far more common in Finland than either Canada or Israel) having a higher alcohol tolerance.

      I found the one saying we’re more likely to be addicted, can’t find either of the actual studies for higher tolerance, but from what I remember the hypothesis is that the same genetics are involved in causing both higher tolerance and higher addiction risk.

      • John Dougan says:

        Given that a large chunk of the northern Europeans 1600 years ago thought heaven was a place where you fought all day and drank all night (and made efforts to create heaven on earth) this isn’t really a surprise. I’d guess there were substantial selection effects in favor of mutations that made that less punishing.

      • Fahundo says:

        I don’t know much about genetics, but since blue eyes are a recessive trait…Uh, I’m not sure how to ask this. I don’t know that susceptibility to addiction or tolerance level would follow the same dominant/recessive model that eye color does. So if my mom had blue eyes but I don’t, should I expect that to affect my tolerance?

        • LPSP says:

          Genetic Dom/Rec is a feature inherent in genetics across the board, and although eyes are a markedly clear-cut case the same line of thought operates elsewhere.

          As for you and your mother: no one gene codes for no one trait. Blue eyes are just one – admittedly highly characteristic – trait of the northern european demographic. If you and your parents heavily resembled this group in many respects, then even if you yourself are missing blue eyes the odds of having a high tolerance are similarly high. The odds are, the genetic coding for all the other traits could easily cause both alcohol tolerance and blue eyes via two independent mechanisms, and just because the blue eye mechanism isn’t active in you doesn’t mean the alco one isn’t as well. On the other hand, if blue eyes are the only nordic-esque trait your mother possesses, it probably doesn’t make much difference.

          And all of this is even supposing that blue eyes and alco-tol are directly connected somehow, and not just coincidentally paired.

      • Deiseach says:

        Various studies mentioned in this article from 2015, including that light-eyed people are more tolerant of alcohol/need to drink more to get the same level of intoxication as contrasted with dark-eyed people.

    • Squirrel of Doom says:

      (18-26 ounces = 0.5-0.75 liter)

      The most terrifying moment on my trip to St Petersburg long ago was buying a half liter bottle vodka, and realizing it was not resealable!

      Which must mean it’s considered one serving!

      • Or that you’re supposed to share it with friends. 🙂

      • Pete says:

        Well, some people do drink 0.5 vodka in a single gulp, but it’s not *that* common except if people just want to get drunk on spot; however, yes, it’s definitely not supposed to take more than one “sitting” even if you’re drinking alone.

        The classic Russian approach to 0.5 vodka, of course, is to split in three glasses (with two friends) and drink the glass as a single shot – so the bottle is done just a minute after opening.

    • Deiseach says:

      Alcohol toleration is definitely real, that’s why when you first drink a small amount will get you drunk and give you a terrible hangover the next day, but if you keep drinking, you get able to “hold your drink”.

      Depending on what they drink and the amounts, I’d believe the Finnish girls (that’s not to say they will be able to keep drinking like that; the older they get, the harder the effects will be on their systems). It’s entirely possible to get up to be able to drink 750ml over an entire day of gin, rum or vodka, not be falling down drunk, and not have a terrible hangover the next day. Compressing that into a night out will make them more drunk (because it’s not spread out over 8-12 hours) but it’s certainly doable.

      Depending on if the Israeli/Canadian girls built up their tolerance on beer, cocktails and lighter drinks and didn’t make a habit of regularly binge-drinking, they might not be as able to handle it.

      As for the effects of a drinking culture, some at least of our alcohol retailers are offering bargain booze to our 17-18 year olds as is now traditional. We’ve always had a problem with underage drinking (where “underage” is “not the legal age of 18”); celebrating the results from the state national exams by going to discos and pubs has become a thing, and of course if you’re in a pub/club, you will probably not be sticking to soft drinks and water. This was even before Leaving Cert students were likely to be 18 (used to be the age range was 17-18). It has now become expected that there will be lots of kids drunk out of their minds the night after getting their results.

      • dndnrsn says:

        It would be interesting to see if the same gap existed between Finnish and non-Finnish men. In my experience, men and women tend to drink differently, with men fitting the “alcoholic” model (drinking at inappropriate times, drinking alone, drinking daily) and women fitting the “binge drinker” model (gets absolutely wasted at parties once every week or two).

    • ADifferentAnonymous says:

      My experience is that subtle mental things can definitely influence alcohol tolerance a lot. If I visit my college, I can pretty much drink like a did in college–for or five drinks mean the night is just beginning. At my home, I drink two and I feel like it’d be hard to drink a third. And if there’s beer for a social thing at my office and I drink just one, I feel off-balance, even though I don’t even notice my first drink if I’m at the college.

      I once read a stronger claim: that while some symptoms of alcohol are objective and physiological, its disinhibition of sexual and violent behavior is basically placebo.

    • Lumifer says:

      The degree of intoxication is dependent on the setting — in particular on food. The effects of alcohol taken together with a lot of food, preferably fatty food, will be slower and less pronounced. On the other hand, mix champagne and vodka 1:1 and drink some on an empty stomach — oh, boy! X -)

    • Balor says:

      It’s not just the amount, but how you drink it. Drinking half a liter or a bit more of vodka in a night would be very doable for a lot of people who think they can’t take that much, if carefully drunk, I think. Start early enough, don’t take a too big dose at any single time so to not throw up. Taking a shot every half an hour isn’t that much. Of course you need basic tolerance to get there, still.

      Not sure which builds up alcohol tolerance faster, binge drinking on the weekend like a Finn or just sipping the same amount spread over a week. But I’d guess the former does.

      My personal guess as a Finn is that we aren’t really more genetically tolerant to alcohol than most people, but genetically more predisposed to binge drinking.

    • Jj says:

      This effect is so obvious as to be conventional wisdom when it comes to psychedelics: the effect of a drug depends on “dose, set, and setting,” goes a common saying. “Set” in that context means “mindset,” i.e. a fuzzy combination of expectations, mood, stress levels, etc, while “setting” refers to the environment, i.e., acid at a rave may work out very differently from in a private, sheltered environment with a trusted “sitter.”

      I see no reason why factors that influence the effect of a dramatic, short acting drug with limited practical applications would necessarily be any different from the factors that determine the effect of a psychoactive chemical that happens to be useful in moderation over time to treat some mental problem. For that matter, I read once (though please don’t rely on this info) that there is some nonlinear effect of combining CBT and SSRIs for certain disorders, as in, the combination works better than the sum of its parts — which is not all that surprising since CBT influences thoughts and thoughts are made of neirons doing chemistry stuff, so why wouldn’t thoughts interact in interesting ways with chemicals?