THE JOYFUL REDUCTION OF UNCERTAINTY

HPPD And The Specter Of Permanent Side Effects

I recently worked with a man who took LSD once in college and never stopped hallucinating. It’s been ten years now and it’s still going. We can control it with medication, but take the meds away and it starts right back up again.

This is a real disease – hallucinogen persisting perception disorder. Most descriptions of the condition emphasize that it’s just some of the visual effects and doesn’t involve distorted reality perception. I’m not sure I believe this – my patient has some weird thoughts sometimes, and 65% of HPPD patient have panic attacks related to their symptoms. Maybe if you can see the walls bubbling, you’re going to be having a bad time whether you believe it’s “really true” or not.

Estimates of prevalence vary. It seems more common on LSD and synthetic cannabinoids, less common (maybe entirely absent) on psilocybin and peyote. Some people say about 1-4% of LSD users will get some form of this, which seems shockingly high to me – why don’t we hear about this more often? If I were a drug warrior or DARE instructor, I would never shut up about this. But if most people just get some mild visual issues – by all accounts the most common form of the condition – maybe they never tell anybody. Maybe 1-4% of people who have tried LSD are walking around with slightly distorted perception all the time.

There’s a lot to say about this from an epidemiological or cultural perspective. But I want to talk about the pharmacology. How can this happen? Why should a drug with a half-life of a few hours have permanent effects on your psyche?

It can’t be that the LSD sticks around. That doesn’t make metabolic sense. And a study discussed here using radio-labeled LSD definitively finds that although a few molecules might stay in the body up to a week or so, there’s no reason to think the drug can last longer than this. I like this study, both for its elegant design and because it implies that somewhere someone got a consent form saying “we’re going to give you radioactive LSD” and thought “sure, why not?”

But then why does it have permanent effects? I know very few other situations where this happens, aside from obvious stuff like “it gives you a stroke and then you’re permanently minus one lobe of your brain”. The only other open-and-shut case 100% accepted by every textbook is a movement disorder called tardive dyskinesia. If you take too many antipsychotics for too long, you can get involuntary tremors and gyrations that never go away, even off the antipsychotic. Although traditionally associated with very-long-term antipsychotic use, in a few very rare cases you can get it from a single dose. On the other hand, most people can take antipsychotics for decades without developing any problems.

Some other possibilities are controversial but plausible. The sexual side effects of SSRIs almost always stop within a few months of stopping the medication, but a few people have reported cases where they can last years or decades. Psychedelics may permanently increase openness and hypnotizability, though it’s unclear if this is biochemical or just that drug trips are a life-changing experience – see my discussion here for more. Also, for every drug that has a mild week-long withdrawal syndrome in the average population, you can find a handful of people who claim to have had a five-year protracted nightmare of withdrawal symptoms that never go away.

So, again, how does this happen?

Every discussion of HPPD etiology I’ve seen is speculative and admits it doesn’t know what it’s talking about. Also, most of them are in gated papers I can’t access. But a few papers seem to gesture at a theory where LSD kills an undetectably small number of very important neurons. Hermle et al talk about “the excitotoxic destruction of inhibitory interneurons that carry serotonergic and GABAergic receptors on their cell bodies and terminals, respectively”. Martinotti seems to be drawing from the same inaccessible source in mentioning “an LSD-generated intense current that may determine the destruction or dysfunction of cortical serotonergic inhibitory interneurons with gamma-Aminobutyric acid (GABAergic) outputs, implicated in sensory filtering mechanisms of unnecessary stimuli”.

This would require some extra work to explain the coincidence of why the effects of HPPD are so similar to the effects of an LSD trip itself. In particular, if we’re talking excitotoxicity, shouldn’t the neurons be stimulated (ie more active) in the tripper, but dead (ie less active) in the HPPD patient? Maybe the tripper’s neurons are just so overwhelmed that they temporarily stop working? Or maybe you could interpret the comments above to be about LSD exciting some base population of neurons, the relevant inhibitory neurons having to work impossibly hard to inhibit them, and then the inhibitory neurons die of exhaustion/excitotoxicity.

Against cell death based explanations, some people seem to recover from HPPD after a while. But this could just be the same kind of brain plasticity that eventually lets people recover from strokes that kill off whole brain regions. The body is usually pretty good at routing around damage if you give it long enough.

What about tardive dyskinesia? When I was in medical school, I was told that the drugs “permanently hypersensitized dopamine receptors”, which is kind of a cop-out – why do they permanently hypersensitize receptors? How come all the other drugs don’t permanently hypersensitize the receptors they antagonize? Apparently now the story is more nuanced. From here:

The pathophysiology of TD is complex and remains unclear. Multiple models have been proposed to explain this unpleasant and sometimes disabling side-effect. One of the first widespread and popular explanations was the theory of dopamine-receptor hypersensitivity. It was suggested in 1970; however, it cannot completely explain the clinical findings, because TS does not generally appear among all dopamine receptor-blocking drugs users.

To date, several neurochemical hypotheses have been proposed for the explanation of TD development. These theories include: (i) a disturbed balance between dopamine and cholinergic systems; (ii) noradrenergic dysfunction; (iii) dysfunctions of striatonigral, γ-aminobutyric acid (GABA)ergic neurons; and (iv) excitotoxicity. Recently, the role of oxidative stress and structural abnormality in the pathophysiology of TD has gained impetus. Induction of free radicals by neuroleptic drugs leading to oxidative stress and resultant structural abnormality could be the key factor in the pathogenesis of TD. The studies by Lerner et al. and Libov et al. support the neurotoxicity hypothesis. This hypothesis has also been supported by reports that chronic neuroleptic treatment increases free radical production and causes structural damage. In 2005, Tan et al. reported that a brain-derived neurotrophic factor appears to exert a protective effect in the nervous system against TD in patients with schizophrenia. There is solid evidence of a genetic predisposition to TD. A study performed by Souza et al. suggests that GSK-3B polymorphism may play a role in the genetic vulnerability to TD manifestation in individuals with schizophrenia.

There also seems to be some sort of role of acetylcholine:

Several studies in animals have reported that cholinergic cells (or the marker enzyme choline acetyl transferase) in the striatum are lost or reduced in amount after prolonged regimes of haloperidol and fluphenazine (49,50). Recently, Grimm and others showed that prolonged haloperidol treatment in rats led to cholinergic cell loss in the specific areas of the striatum related to oral movements (51). This result may provide an animal model to explain why TD in humans is most commonly a motor disorder of orofacial musculature. Proton magnetic resonance spectroscopy provides supporting evidence for the cholinergic hypothesis. This method allows quantification of choline, the precursor of acetylcholine, in specific brain structures. Choline reuptake leads to the accumulation of choline in cholinergic neurons before its conversion to the transmitter; an excess of choline in brain tissue will signify a loss of cholinergic neurons. Using this method, investigators have shown that, in schizophrenia, choline levels in the basal ganglia are greater than normal (52). Ando and others produced further results with this method (53), implying that choline levels in the lenticular nucleus are higher in schizophrenia patients with TD than in those without the syndrome.

Apart from such methods for assessing cholinergic processes in the striatum, clinical trials with cholinergic agents in patients with TD could provide indirect evidence related to the cholinergic hypothesis (44). Caroff and colleagues showed that the anticholinesterase donepezil was effective against the symptoms of TD (54,55). Since choline, the precursor of acetylcholine, was not effective, Caroff and others regarded their evidence as support for the hypothesis of Miller and Chouinard. However, a recent metaanalysis concluded that trials of cholinergic agents in the treatment of TD conducted to date have insufficient statistical power to reach a firm conclusion about the drugs’ effectiveness (56). This area of research may be clarified when cholinergic agents effective against specific muscarinic receptors are tested in patients with TD.

So apparently it’s a conflict between a receptor hypersensitivity hypothesis and a killing-off-interneurons hypothesis that resembles some of the work around HPPD?

I’m biased in favor of killing-off-neurons hypotheses because they’re comfortable and they make sense. Of course if a drug kills something, it’s going to permanently impair function. This makes the idea of “drugs with permanent side effects” a little bit less scary, restores us to the “some medications cause strokes and then you’re screwed” realm of everyday life.

The alternative is thinking of the body as a chaotic system which settles into various attractors. Take the wrong drug and you can push yourself into a different attractor state, which will persist until something shifts it. This definitely seems true of some things, and is one of the ways I think about depressive episodes – which can last months or years, and which can be precipitated by some sort of obvious stressor (getting fired, breaking up, being bullied) but last long after the stressor is gone. If this explains permanent drug side effects, it seems somehow scarier to me than the other option. It’s not just that you have to make sure not to accidentally kill any cells. It’s more that nobody has any idea what the underlying mechanisms look like, anything can happen, and you just have to hope you don’t screw up.

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127 Responses to HPPD And The Specter Of Permanent Side Effects

  1. vrostovtsev says:

    For the HPPD patients that have panic attacks related to their symptoms — is this treatable? Would a hypothetical patient with this issue require a doctor that has a special skill set or would any good specialist be able to address the issue?

  2. ledicious says:

    If I were a drug warrior or DARE instructor, I would never shut up about this.

    I just assumed that HPPD was the basis for the tales of LSD flashbacks.

    • Leah Velleman says:

      I had this same thought: when I was in school, DARE et al didn’t shut up about flashbacks. They also insisted that taking too much LSD would make you permanently tripping and you would never come back down, which definitely sounds like an account of HPPD filtered through a DARE instructor’s brain.

      • M says:

        This might also be in the same line as when I was a kid and made funny faces, my mom would say “Don’t do that or your face will freeze like that.”

  3. quanticle says:

    If this explains permanent drug side effects, it seems somehow scarier to me than the other option. It’s not just that you have to make sure not to accidentally kill any cells. It’s more that nobody has any idea what the underlying mechanisms look like, anything can happen, and you just have to hope you don’t screw up.

    It’s interesting that you think this is the scarier option. To me, it seems like it’s more hopeful. Yes, you’re stuck in a bad attractor now, but if we can just figure out how to give your body the right kind of jolt, we can get you back to how you used to be. Cell death, on the other hand, is permanent. You had neurons here, now you don’t, and if you lack sufficient brain plasticity, you’re just screwed forever.

    • vrostovtsev says:

      Maybe if we can figure out how, we can give regular humans the ‘more right’ jolt and end up with a better baseline for human condition, a Strugatski brothers’ fictional ‘fukamization procedure’.

    • theBearwithThrust says:

      I agree with Scott on this. The scary part of the chaotic explanation is that it implies the possibility that a person can go mad for no apparent reason. Imagine this, one day, a completely normal person is driving along a crowded street, and he suddenly lose his mind and decides to run over people. All of these happened because of a random ad on one side of the street which somehow triggers his brain. And this can happen on anyone while we may not be able to notice.

      To kill some cells, at least we have to intake some medicine or get hit somehow.

      • Andkat says:

        Plenty of cases of depression and other psychiatric conditions arise without any sort of well-defined insult (even if the long term consequences of depression involve atrophy)- people ‘go mad’ inexplicably all the time. Schizophrenics can certainly get massively behaviorally affected by distorted perception (i.e. the TV talking to you, the newspaper addressing you) of innocuous phenomena. Not to mention that cells can just…die stochastically. Oxidative damage or freak hydrolysis cascade, double strand break, whoops couldn’t repair it in time, apoptosis! All distinctions of this kind are quantitative rather than qualitative in nature- there are innate physical properties and regulatory mechanisms in play that dictate the probabilities of different events and runaway global transitions resulting therefrom. Whether it be DNA repair or biomolecular switches regulating neurochemical flux, the body is designed to buffer against physicochemical ‘noise’ – major perturbations especially when leveraged against genetic inadequacies can be enough to override those and throw things off balance. The fundamental implications don’t change if the states we are considering are of intracellular regulation, cell life/death, or neurochemical fluxes, etc.. All that matter are the quantitative thresholds, the probabilities of experiencing a runaway transition to an undesirable state given a particular type and magnitude of perturbation (which we are very far from any kind of exhaustive quantitative understanding of for this system).

      • vV_Vv says:

        Imagine this, one day, a completely normal person is driving along a crowded street, and he suddenly lose his mind and decides to run over people.

        This is not how chaotic systems work.

        The weather is a chaotic system. Does it mean that one day there is good weather, then suddenly a hurricane strikes out of nowhere? Nope.
        While the proverbial butterfly can indeed cause a hurricane, it doesn’t happen overnight. You can notice the build up. And hurricanes can’t happen anywhere, different places have different hurricane risk.

        As for people who run over people, there are known risk factors and usually there are warning signs if you pay close attention. Why one specific person ends up doing it while many others with a similar risk profile don’t is indeed likely due to chaos.

        • Peter says:

          It’s also worth being cautious about “no reason” with chaotic systems. Consider for example snow. In the parts of the UK I’m from, it typically snows about two or three times a year. You can predict years in advance that the days it does snow are much more likely to be in February than in August, and it’s not hard to figure out why; predicting exactly how many days and which exact ones needs to be done a lot closer to the time and is much less reliable.

          So if it snows on the 4th of February you could say there’s an obvious reason for the “February” bit but not so much for the “4th” bit.

        • theBearwithThrust says:

          Admittedly, the example I made is indeed a very extreme and unlike case. However, the point I was trying to make is, like mentioned in Andkat’s comment, people can get mental issues without any apparent reason. Like you said, we can create tools / measurements to predict which group of people this is more likely to happen upon. But, it seems impossible to tell how I, as an individual, can avoid such situations.

          • vV_Vv says:

            But, it seems impossible to tell how I, as an individual, can avoid such situations.

            But this is generally true of all sorts of hazards. You can mitigate the risk (e.g. by wearing seatbealts, not taking hallucinogenic drugs, etc.), but not completely avoid them.

        • Controls Freak says:

          This is not how chaotic systems work.

          *Puts on pedantic hat.*

          Noticing that one particular chaotic system has observables which allow human-timescale prediction of hurricane-scale events does not imply anything about observability characteristics of phenomena at different scales in other chaotic systems. I'm not saying that you're wrong about humans and risk factors (I'm maybe somewhat agnostic here). I'm saying that, "This is not how chaotic systems work," is too general to the point of being incorrect. Basically, we have neighboring trajectories diverging exponentially. That doesn't say much about the scale of the attractors in question, the variables amenable to observation, or the relevant timescales (essentially, Lyapunov exponents compared to some measure on the other features). At least not in general.

          • vV_Vv says:

            I’m saying that, “This is not how chaotic systems work,” is too general to the point of being incorrect. Basically, we have neighboring trajectories diverging exponentially. That doesn’t say much about the scale of the attractors in question, the variables amenable to observation, or the relevant timescales (essentially, Lyapunov exponents compared to some measure on the other features).

            Yes, each system has its own relevant time scales and variables more or less amenable to observation, but I was responding to a comment which I interpreted as meaning essentially “chaotic system => unpredictable black swan events”, which is generally not true.

          • Controls Freak says:

            Agreed. Like I said, I was only being pedantic about the one sentence which was too general.

  4. SEE says:

    I know I was warned about LSD causing HPPD and flashbacks when I was in middle school. Maybe your school district just cared less about your long-term mental health?

    • Viljami Virolainen says:

      Psychedelic use correlates at population level with better long-term mental health, not worse.

      • Yaleocon says:

        Sounds plausible. Compare population A, where use of psychedelics is above average, to population B, where illegally-obtained Oxy is the drug of choice. Just based on stereotyping (A=college students, B=the lower-class unnecessariat), A is probably richer on average, and better mental health could follow. The same probably goes for cocaine (as opposed to, e.g., crack).

        Note, however, that I won’t be advising my children to do cocaine; it wouldn’t make them richer or happier, because that’s not how the causation runs. The same goes for LSD. “Correlation at the population level” and “causation at the individual level” are two gigantic massive steps removed from one another, and saying “don’t do drugs, kids” is still a good idea.

        So Viljami, whatever point you thought you were making contrary to SEE, I’m interested to hear you lay it out in further detail, preferably avoiding the massive pitfall you encountered on your first try.

        • deciusbrutus says:

          There’s a difference between saying that correlation at the population level does not imply causation at the individual level, and establishing causation at the individual level.

        • Viljami Virolainen says:

          Maybe you should do your homework before posting instead of pulling speculation out of your ass. Cocaine use does correlate with mental health problems at population level even though it is perceived to be an upper class drug. Alcohol use (when above moderate), tobacco and even cannabis use correlates with mental health problems at population level.

          When you take previously mentioned facts into consideration the fact that psychedelic use does not correlate with worse mental health at population level is at least weak evidence pointing to the direction that it might not be as harmful for your long term mental health as the popular knowledge would make us assume.

          Of course there is also increasing amount of evidence on the possible mechanisms of how psychedelic use can actually be beneficial to people. But that is not an argument I would use as a first line of attack on somebody who is still stuck with the popular folk idea of the subject. It would probably just make them dig into their trenches and suspect everything I say after that.

  5. UFyyy2 says:

    You are talking about a substance with an effective dose of 100-150 MICRO grams being manufactured by people who generally lack access to lab grade reagents and analytical chemistry lab equipment. Additionally one of the main reagents is synthesized from a fungus.. It isn’t too hard to imagine a freak impurity causing a negative side effect or a side reaction that changes the efficacy of LSD leading to those fluke side effects.

    Too much messing around on the side chain of some molecules can be really disadvantageous. For instance I have only heard REAL bad things about anyone that has experimented with any ‘Research Chemical’ that is derivative of THC. While on the other hand I’ve seen just about everything and the kitchen sink attached to cathinone (Khat) and avoid most serious side effects.

    FWIW LSD and LSA are the only two Lysergamide based hallucinogens I’ve heard of people using safely, but there are apparently some other know analogues, and I haven’t really dug into the reaction to speculate what specific effect an impurity could cause.

    p.s. I would have pegged HPPD as a perfect analogue of schizophrenia. Which is why I always get so confused at research papers that use Ketamine in animal research to model schizophrenia; LSD always seamed more apt.

    • cactus head says:

      >For instance I have only heard REAL bad things about anyone that has experimented with any ‘Research Chemical’ that is derivative of THC.
      Why is it that THC itself is comparatively good?

      • Doug says:

        > Why is it that THC itself is comparatively good?

        This is a very interesting question. Almost all drugs in the cannabinoid class have reputations for being physically dangerous, more addictive, less pleasant, and more prone to serious mental breakdowns. If anything, it seems the cannabinoids as a class may be the worse of all the major recreational drug categories. Worse addiction than opiates, worse withdrawal than benzos, more antisocial behavior than stimulants, more insanity-inducing than the dissociatives.

        Yet THC stands completely apart. It ain’t green tea, but it’s pretty much the most benign drug that’s still fun. Tweak the THC molecule even a little, and things just go off the deep end. At best, maybe you get something that doesn’t seem like it was invented by satan, like JWH-018, but still is a lot worse than THC.

        It’s just so weird and coincidental. The cannabis plant has no specific reason to make the one cannabinoid out of all possible chemicals in the family that Homo Sapiens is totally cool with. It’d be like if the poppy plant made the perfect non-addictive opiate that no one could overdose on, yet is still subjectively better than every other opiate in the space of all opiates.

        • nameless1 says:

          Why is JWH-018 particularly bad? It is one of the ingredients in Spice and Wiki is pretty moderate about it.

          • Doug says:

            Sorry, maybe was a little unclear. I was saying that JWH-018 is one of, if not the most, moderate cannabinoids. But even then, it’s safety profile, both physical and mental, is still significantly worse than THC.

        • Yaleocon says:

          We domesticated fun friendly dogs out of vicious wolves. And I thought I heard we kinda did it unintentionally–our presence created selective pressure for wolves to go from pack-hunting badasses to cute happy puppers, and time did the rest.

          I am ignorant beyond words about evo-bio, pharmacology, and marijuana. But I’ll speculate wildly anyway–is there any evidence for or against the possibility of something similar happening with cannabis? Earlier humans could intentionally cultivated the most fun and least dangerous strains of the plant. Or even could have just consumed the most fun and least dangerous ones and spread the seeds in their scat, unintentionally creating selective pressure for being “good for humans.”

          Although just eating marijuana doesn’t produce a high, right? That would be a serious strike against. Maybe it’s just a miracle. Hmmmmm.

          • ADifferentAnonymous says:

            Not an expert either, but I know that generally speaking it is preferred that marijuana for consumption not contain seeds*. So could be that humans consuming it have always discarded the seeds, possibly in opportune places for the plants?

            * D.R.E. et al., 2001. https://genius.com/7597

          • Enkidum says:

            There’s two things to consider with regards to seeds.

            First, if you want high potency bud, you’re best off having unfertilized female buds, and thus no seeds (from what I understand, this is purely because the plant spends energy producing seeds that it would otherwise devote to growing bigger flowers/buds). However this requires no male plants within, uh… pollination distance – I have no idea what the correct term is, but the male’s pollen can easily be blown hundreds of meters to fertilize. This is one of the reasons why indoor-grown weed tends to be far more potent, because you can ensure that all male plants are weeded out long before they’re capable of pollinating anything.

            The second reason is simply that if you set fire to weed with seeds in it, they have a habit of exploding, which can be annoying.

            I suspect the first reason was not something that could have affected things on an evolutionary timescale, because it requires an awful lot of knowledge about how plant sex works, etc. The second, however, very well could work. You have caveman stoners picking the seeds and throwing them out before putting them in their pipe, that kind of thing, much as people buying shitty Mexican weed still do today.

        • tatarerike says:

          Another possibility is that we only use marijuana because THC isn’t too bad; if the compound the plant uses for whatever it uses THC for did happen to be one of these ‘invented by Satan’ drugs, maybe we would have stuck to using hemp for rope and smoking it never would have become popular. Compare to datura or morning glory seeds.

      • Lambert says:

        IIRC, it only partially agonises whatever receptor it affects. Synthetic cannabinoids bind much more readily, making them hundreds of times stronger. (Not just in a ‘you only need 1/100 as much’ way. The receptor response vs dose plateaus before any really bad stuff happens, IIRC.)

    • wintermute92 says:

      being manufactured by people who generally lack access to lab grade reagents and analytical chemistry lab equipment

      Are you sure this is true of LSD? It’s true for many drugs, certainly, but precisely because LSD is so touchy and low-dose, it tends to come from a relatively small number of manufacturers making big, clean batches. And since the batches are so large, bad batches actually develop reputations and stop selling. For all people say that drug dealers will never tell you “this stuff is dirty, come back tomorrow”, they were making public announcements at Woodstock about avoiding the “brown acid”.

      Owsley Stanley set up a lab in California and then one in Colorado in the 1960s, and made 5,000,000 doses worth of acid himself. William Leonard Pickard ran a massive production ring with labs around the West Coast, though the exact scale is disputed. The equipment he was busted with was all commercial-grade lab hardware. Nicholas Sand turned an old farmhouse into a lab and cranked out 3,000,000+ hits, and he was a good enough chemist to effectively pioneer DMT synthesis.

      As far as I know, LSD manufacturing is one of the few exceptions to the “amateurs in dirty basements” basis for drugs, and unlike STP or other rare hallucinogens the dosages are pretty well understood. My guess would be that widespread bad reactions are to the drug itself, not to manufacturing errors.

      • naughtyhash says:

        precisely because LSD is so touchy and low-dose, it tends to come from a relatively small number of manufacturers making big, clean batches

        I tend to believe this in theory, but realistically, the fact that there are bad batches at all indicates either that the manufacturing process can go wrong even in the best of labs, or that there are some dodgy manufacturers.

        In reality, I’d imagine it’s some combination of both. Either way, it seems plausible that impurities could at least be a candidate for explaining HPPD.

    • Doug says:

      I don’t believe there’s any evidence of biologically active impurities found in street LSD. (I’m not talking about other drugs like DOB or NBOMe explicitly sold as LSD.) The brown acid at Woodstock, like many such cases, was a myth. It was perfectly fine, in fact dosed quite heavily. Then it was handed out to a bunch of neophytes in the hot summer, who had a bad trip and assumed that it was the chemicals’ fault.

      LSD synthesis is such a delicate process, that if you screw up, you don’t get LSD+impurities. You just get nothing.

      • themindgoo says:

        I’ve heard that it’s possible to have unreacted ergotamines in the final product if you are not careful with chromatography

    • Patrick Cruce says:

      If an impurity caused the problem then HPPD would occur in clusters; like the case of the frozen addicts. I don’t believe it does.

    • skef says:

      The fundamental difficulty posed by the impurity hypothesis is that the impurity in question would need to cause its symptoms at the extremely small concentrations of a typical LSD dose. The possibility that a substance could do damage at such concentrations with little or no subjective effect seems remote — LSD’s potency is mysterious but it’s somewhat plausible that it might have permanent effects given he strong temporary ones.

      The remaining possibility is a substance that causes subjective effects quite similar to LSD at similar doses as LSD but that also causes damage, which is possible but unlikely given the coincidence and, as Patrick Cruce points out, the lack of evidence of clusters.

    • Cheese says:

      “p.s. I would have pegged HPPD as a perfect analogue of schizophrenia. Which is why I always get so confused at research papers that use Ketamine in animal research to model schizophrenia; LSD always seamed more apt.”

      LSD/HPPD isn’t a good model of schizophrenia – it’s kind of a common misconception that it is I think.

      Scott will know more about this than me, but visual hallucinations and visual disturbances are really, really unusual in schizophrenia. It’s one of the important psychosis vs delirium/drug induced clues when you’re trying to decide which one it is. Which is kind of the main thing that HPPD gives you. Schizophrenia hallucinations are nearly always auditory, and you’re always going to have some kind of formal thought disorder (i.e. that’s required for the diagnosis), which you don’t find in HPPD.

  6. ilikekittycat says:

    The Hallucinations were coming from inside the house the whole time conjecture: I have no idea if my situation applies to any other brains, but what I noticed on psilocybin was, I became a lot more aware of body processes in that state (or less able to ignore them) and the knowledge that they were occurring carried through to my life after the trips. Now I can sometimes see the edges of things getting blurry, or like, the stucco seeming to “smear” into less prominent peaks for a moment when I’m not focused on it, or the branches of trees seeming to “grow” to the horizon fractally in very low light conditions after the sun has gone down if I stare unblinking, or particles of dust that float too close to my eye getting mistaken for the signature wiggle of a rattlesnake in the edge of my vision. As a rational person, I know blood is pumping through my eye, and I am able to remember the imperfect conditions of the distorted organic lens I use to see.

    I have 0 epistemic certainty here, but my hunch is that, much like the brain reconciles memories that don’t make sense to it into a consistent narrative, everyone is “seeing” more minor visual field errors day-to-day than your brain “remembers” seeing in normal life… and becoming aware of this inconsistency permanently ruins certain peoples’ days, because your brain near-instantly retconning things every single day sounds unnatural and feels like something is being forced upon you, like a hex

    • LTK says:

      If that’s the case, wouldn’t other hallucinogens like psilocybin have the same effect? Why does LSD especially cause a failure of visual retconning?

      • wrinkledlion says:

        I don’t know that they don’t. After taking shrooms a few years back I noticed that I could make the floor “breathe” if I stared at it long enough with a blank mind. This was a regular thing for a few months after, and even now I still find it happening on occasion. It doesn’t cause any distress, it mostly happens if I’m trying to meditate or somesuch.

  7. gloster80256 says:

    I strongly suspect a connection between HPPD and the top-down (predictive) and bottom-up (sensory) consciousness streams theory. (Can’t remember the name of the post. It had a lot of Paris in the the springtimes in it…)

    (In phenomenological terms – not necessarily corresponding to the exact mechanisms) The trip effectively gives the dream-like reality predictor precedence over the raw sensory data which results in the mind constructing wild phantasms out of minimal stimuli, similar to certain symptoms of schizophrenia. HPPD (where you often see e.g. “snowing”, waving or flowing effects over textured surfaces) seems like a continuing disbalance between the two streams in favor of the hallucinatory state – as if the predictive stream was anticipating motion and the sensory stream was failing to correct it. I strongly suspect the trip might just leave the calibration out of whack, to a greater or lesser degree. (The mechanism – and here I am totally speculating – could be just a stronger learned preference for one source of signals in the “visual processing center”.)

    • Virbie says:

      > I strongly suspect a connection between HPPD and the top-down (predictive) and bottom-up (sensory) consciousness streams theory. (Can’t remember the name of the post

      I think it was the book review of Surfing Uncertainty?

  8. Psycicle says:

    Anecdote time: The only psychedelics I’ve used are Mescaline/Cactus Juice, and HBW seeds, and I got a low-key form of HPPD for… 2 years now, after a mescaline trip (and it wasn’t a huge dose, either). I can actually conciously toggle it on and off at will (it is default-off, except late at night on modafinil), and in the on-state, computer text appears a little wavy and wiggly and ripples a bit, like the almond illusion. The text remains perfectly legible.

    In other words, I don’t buy that mushrooms and peyote are free of HPPD, they’re probably just less prone to cause it, or cause milder forms of it. (synthetic phenethylamines, like 2C-E and the NBOMe’s, are typically what I’ve heard are prone to causing HPPD, at least from snippets of drug user folklore)

    2/3rds of people having panic attacks due to it seems much too high, probably due to only the worst cases of HPPD making it into the medical system, where it actually affects quality of life. The people with minor visual effects aren’t going to be visiting a hospital or psychiatrist in response to occasional nifty visuals.

    • dick says:

      I might “suffer” from this, if that’s the word, as well. I’ve done LSD a dozen or two times, about 20 years ago, and ever since then if I stare at any large patterned surface like a wall or carpet, I can see wavy/ripply distortions very similar to the almond illusion Psycicle linked to. Unlike Psycicle, I’ve never done peyote, mescaline or HBW seeds (whatever those are), just acid and mushrooms and pot. I experienced quite different visual hallucinations on mushrooms (floating, shifting geometric shapes which are unrelated to whatever I’m looking at), but only while I was actually on the shrooms.

      While I can’t swear this is HPPD or even that it was caused by LSD, I associate it with LSD because I clearly remember a much more noticeable version of the same hallucination during several of my trips. I realized I could see them while not tripping long ago, after my first few trips, and initially worried about it, but they have not gotten more or less intense since then and these days I forget about it for months at a time. I can “dismiss” them easily, and they’re not alarming, except for their unexplained nature.

      There’s my n=1!

      • Fluffy Buffalo says:

        …and ever since then if I stare at any large patterned surface like a wall or carpet, I can see wavy/ripply distortions very similar to the almond illusion Psycicle linked to.

        I get the same effects when I stare at patterned carpets, and I’ve never taken any drug stronger than caffeine. So I doubt it’s really related to HPPD.

      • nestorr says:

        I’ve never done any drugs but I’ve known for a long time* if you stare at walls or tile patterns or stuff your vision will start to do funny stuff, it’s called retinal fatigue or something like that, I often wonder if a lot of the effect of psycho-actives is to just make people passive enough to trigger the kind of perceptual aberrations that would happen anyway if they just sat still for long enough (See also meditation)

        *I was doing that in a park once and an acquaintance walked by and talked to me, and from 3rd parties I’m told he was convinced I was on drugs. Nope, natural high bby!

    • Doug says:

      I’ll second the ability to “melt walls at will”. Back during my days of regular psychedelic use, I would be able to focus on a scene and get the classic wavy borders effect. (Very similar to looking at this http://brainden.com/images/static1-big.jpg) Particularly when I was hung over from drinking and stared at the same thing for long enough.

      It wasn’t permanent or intrusive, just kind of like the ability to realize that the machinery in brain was stabilizing the image, then being able to turn off the filter. Sort of like the spinning ballerina silhouette GIF (assuming you can make your brain reverse her direction).

      Nowadays that I’m old, boring and sober, this super-power has faded completely away.

    • ilikekittycat says:

      This “almond illusion” basically matches the varieties of my post-hallucinogenic hallucinatory experience.

      Do you “toggle” this state by focusing as if to decipher a magic eye pattern?

      • Psycicle says:

        It’s actually more of a feeling of defocusing a little bit and not holding my attention on the letters as sharply as I normally do.

        • Yaleocon says:

          Never taken hallucinogens, but I can do exactly that “defocusing” with the almonds to make them stop their freaky wavy wiggling. I’d speculate (still n=1, but with a control now!) that what you experience with text is exactly what most people are experiencing when they look at those almonds.

          • Helaku says:

            I also can “stop” the motion of almonds if I stare enough. My ad-hoc hypothesis is that saccades are somehow may be involved in “freezing” the image. Though I cannot make up any decent mechanism of this.

            Edit: Colonel Hapablap gives reasonably sounding hypothesis below.

    • themindgoo says:

      I somehow had something similar even before I had used any drugs. Quite often if I look at the floor or wall I can cause it to become wavy or slowly rotate and sometimes it has those colors that you can see with closed eyes.

    • Colonel Hapablap says:

      I have the same sort of hallucinations and I’ve figured that it is all related to having easily created after-images. I can see a quick afterimage after looking at something dark for a split second and then looking at a blank light background. I suspect the patterned carpet-breathing effect is caused by strong afterimages mixing with the current image, creating a segmented 3d effect in the same way that a magic-eye picture works.

  9. actinide meta says:

    Could HPPD just be the result of learning? Like, maybe normal perception requires some extremely strong, but learned, prior (“the walls are NEVER melting”), and for some people a few “counterexamples” seen under the influence of LSD are sufficient to learn that the prior is not always true?

    Analogy: A coworker of mine once complained that their new projector had color alignment artifacts that shifted depending on his viewing angle. Another coworker listened to his description of the symptoms and correctly diagnosed that what he was really seeing was chromatic aberration in his eyeglasses. The first guy, on realizing that this was true, now could see the same artifact everywhere and joked that this ruined his life…

    • herbert herberson says:

      Definitely think this is it.

      Speaking as someone who has experienced minor “flashbacks,” the subjective experience is very similar to being able to see “magic eye” illusions–it feels like a developed skill, a trick to seeing things in a certain way

    • soreff says:

      Another coworker listened to his description of the symptoms and correctly diagnosed that what he was really seeing was chromatic aberration in his eyeglasses. The first guy, on realizing that this was true, now could see the same artifact everywhere and joked that this ruined his life…

      Same here…
      My eyeglass prescription is strong enough that if I want to see a small purple
      object as purple, I need to look at it right in the center of my visual field.
      If I look at it off-center, chromatic aberration separates it into two images,
      one red and one blue.

      • deciusbrutus says:

        Does that apply to all purple objects equally, or differently to ‘purple’ objects displayed on a RGB or CYM light-producing thing?

        • The Nybbler says:

          There’s no monochromatic purple, so it should always apply.

          • Ghillie Dhu says:

            Do you mean that, since neither RGB nor CYM produce monochromatic purple they’d both separate?

            I would expect that light with wavelengths between 390 & 455 nm (i.e., monochromatic purple), would not separate through the glass despite partially activating both the red- & blue-sensitive cone cells in the viewer’s eye.

          • The Nybbler says:

            Between 390 and 455 is violet, which wouldn’t separate. But many of the hues we call “purple” can’t be produced by monochromatic light, so anything we see as those purples will separate in the light in which it is visible.

  10. amaranth says:

    FUD

  11. Nancy Lebovitz says:

    I’m going with the learning model, with the hope that more learning can solve at least some of the problems, as with people learning not to have phantom limbs.

  12. Imperatrix says:

    The one I have always wondered about is some sort of immunologic issue. We know there are immunologic causes of neural disease that go after neural receptors (e.g. Lambert-Eaton, Myasthenia gravis). I have always wondered if maybe LSD or the like might present something to microglial cells and trigger some sort of immune modulation (e.g. 5HT binding LSD results in the immune system going after that “epitope” and then having some cross reactivity with 5HT in general).

    This would fit with why there is intense variation in response, why the process can extinguished (e.g. some form of induced anergy), and repeated exposure makes it more likely.

    Now granted this is all rank speculation by an amateur, but I have wondered for a long time if we might have some CNS counterparts to a lot of the systemic autoimmune conditions that target receptors. I have not read of too much work being done on neuroimmunology, but that likely reflects my ignorance more than the state of the field.

    • Cheese says:

      If it was auto-immune in any way you would generally expect it to be progressive once it begins. If it was serotonin cross reactivity, I can’t see that being anything but an absolutely massive shit-storm once it begins.

      Hallucinogens are fairly interesting with respect to their mechanism of action. I mean that in the sense that they probably work by having some weird effects and receptor level that your endogenous ligands don’t have (in terms of receptor polymerisation, odd functional selectivity), and then their downstream effects are even weirder (and we really don’t know a lot about). There’s a hell of a lot of steps there where something might be able to be pushed out of equilibrium compared to your relatively simple re-uptake inhibitor, releasing agent or agonist categories that a lot of other psychogenic drugs fall into. And even then with something like SSRIs we know the actual clinical effect is like 5 or 6 steps away from the actual mechanism of action.

  13. Doug says:

    > It seems more common on LSD… less common (maybe entirely absent) on psilocybin

    Is there firm evidence behind this? Because it really doesn’t seem consistent with my personal experience or the widely reported subjective differences between the two. LSD isn’t exactly a tea party, but psilocybin’s well known for producing much more intense mind fucks. The thought loops and confusion are much deeper than the typical acid trip.

    The only thing I can see LSD having going for it is the longer duration. Maybe intensity of the experience matters less than just total time.

    I’d be curious if there are any known HPPD cases related to 2C-B use. This is basically the opposite. A visual psychedelic, which is known for being an extremely easy and mentally unchallenging trip.

    • herbert herberson says:

      I think it makes sense in that the biggest difference between LSD and mushrooms isn’t really qualitative, but rather the fact that there is no ceiling to acid–even though the “standard” experience is pretty similar for both drugs (and to the extent they aren’t, I am with you in that, personally, I find mushrooms to be more psychologically intense/uncontrollable despite their more benign reputation), if you want to you can take truly massive doses of acid, while taking too much more than a standard dose of mushrooms will mostly just result in a pile of vomit with lots of psilocybin in it.

      So, while the minor “flashbacks” might come up in comparable amounts, the ones significant enough for people to seek medical assistance and enter the literature would be much more likely to come from acid. I’d certainly bet dollars-to-donuts that Scott’s friend didn’t develop his condition from taking a couple hits at a festival!

  14. Maxander says:

    Regarding the last paragraph; this sounds like it’s connected to the lead article. It turns out that the brain can modified for indefinite periods of time through slight-seeming perturbations that we don’t understand and can’t always even perceive; eek!

    The belief “biology is chaotic and complex and we don’t understand it” is sort of like believing in a fickle personal God, in that it is consistent with just about anything and allows for anything to happen. It offers no constraints, so we’re reduced to essentially superstitious behaviors to navigate the world (“You can eat these chemicals, but it you eat this other chemical, you might get cursed” “Why? And how do you mean ‘cursed’?” “Dunno, it’s something about neurotransmitters.”) Unlike belief in God, though, the present scientific consensus is that this is true, so we’re just stuck with being primitives (and funding the NIH.)

    Regarding the mention of the radioactive-LSD consent form; that seems like a really easy study to recruit for, you just need to find a bunch of stoners who want to become superheroes. The IRB can’t get you for not saying that you won’t become Superman (I think.)

  15. Ashley Yakeley says:

    Does a subsequent LSD dose ever cure the HPPD? If so, this would point to the “chaotic attractor” theory.

  16. Andkat says:

    In terms of conceptualizing an ‘attractor hypothesis’- I think it is worth considering precisely what sort of mechanism might be at work. One might imagine simply that given the complex feedback loops and hypersensitive switches involved in the neurochemical signal transduction cascade that a perturbation to the (ensemble of) neurochemical steady states for a particular circuit that stochastically fails to relax back to the critical threshold to switch back to normal will just keep spinning its wheels in an LSD-like steady state, without exerting any other sort of memory effect. However, it perplexes me that nobody is explicitly articulating an intuitive culprit in any sort of memory effect- epigenetic modulation. I’ve seen plenty of putative drug mechanism that loop back into modulation of e.g. MTOR and thus implicitly into transcriptional regulation- it is conceivable that this may get ‘pushed too far’ in some people resulting in a state of persistent chromatin suppression or stabilization in functionally relevant genes in particular neurons beyond a threshold where they are likely to relax stochastically thereby altering their long-term behavior which then calcifies into enduring changes to the neural steady state, for instance .

    Aberrantly persistent cellular-scale memory effects seem like they could easily be relevant- biochemical processes are stochastic and individual genetic and path-dependent developmental variation will mean that some people will have a significant chance to have processes get ‘stuck’ in certain equilibria/steady states that most people have a high chance of avoiding. On top of which LSD and many other small molecules will generally have some finite range of possible ‘off-target’ binding – some people may have incidental genetic sensitivities that are functionally relevant (i.e. ‘off-target’ LSD binding has both a functional effect and on something important on top of that). In addition one might imagine variable sensitivity between individuals to other forms of cellular memory in the brain such as i.e. synaptogenesis in response to a transient but intense change in neurochemical flux caused by a strong drug response, perhaps with a context dependency (how often do people get HPPD from ‘bad trips’ vs. ‘good trips’ etc.).

    (Disclaimer- I’m not a neuroscientist or a systems biologist, I have just enough overlapping background to ramble dangerously- someone with real knowledge of some of the relative timescales and thermodynamic sensitivities of important checkpoints relative to the scale of characterized drug-induced perturbations for the processes above would be better positioned to evaluate the likelihood thereof….)

    I’m not sure if it makes sense to differentiate ‘biochemical’ vs. ‘psychological’ changes- the operating system is biochemistry, all changes are manifested in the biochemical configurations of the brain itself, on some scale. The question is simply through or in what circuits, consciously or sub/unconsciously associated, the changes are being effected by, no?

    On the matter of LSD- I’ve heard incidentally of what is sold as LSD often comprising or being adulterated with other psychdelics; and I do not know how many of the more pharmacological-standard labs are still operational.

    Speaking as someone who got visual snow probably by too rapidly dropping a psych med, it’d be real swell if someone could figure this out and report back to me with a drug candidate to fix it, preferably by the end of the next week.

    • Cheese says:

      This would be my bet for a mechanism if it is not one related to excitotoxicity in a few key population of neurons (which is a pretty plausible hypothesis on face value tbh). The problem when you start talking about receptor disruption and changes in signalling is the chronicity of the problem. A bit of inappropriate epigenetic changes in a specific sub-population of neurons is a good solution. There’s a lot of research in mood disorders which shows changes in splicing and editing in receptors is one probably component of the problem.

  17. Alkatyn says:

    I’ve been thinking of trying LSD or other hallucinogens for a while, but this is making me reconsider. Do you think the percentage of users number is accurate? Do other hallucinogens have the same issue or just LSD?

  18. Fluffy Buffalo says:

    This is speculative, but: a while ago, you wrote a review of “Mastering the Core Teachings of the Buddha”, where Ingram claims that through meditation, you progress through mental states in a fairly predictable manner, and these states have effects that don’t stay confined to meditation, but bleed through to everyday life and can last for months or years (he mentions the “dark night of the soul” as an undesirable state that some people get stuck in). He also claims that you cycle through these states repeatedly as you progress in your practice. That sounds a lot like the “attractor states” model is applicable at least to some aspects of brain activity, and that meditation practices offer means of pushing the practitioner from one to another. Seeing how psychedelic experiences are reportedly often of a similar nature as spiritual revelations from meditation, is something similar going on here? Are HPPD sufferers like “dark night yogis”?

  19. Aapje says:

    There was a story in my newspaper recently about the Malaria-drug Mefloquine possibly having a relatively large chance to trigger long-term mental health problems such as depression, hallucinations, and anxiety. The person being featured had to be given several electroshock treatments to cure her depression.

    A story about it.

    PS. Note that phase III safety and tolerability trials were skipped because the military had a high need for a new Malaria drug.

    • Fluffy Buffalo says:

      That stuff is known to be bad. Nightmares, depression, possibly suicide and murder… the works. From what I heard from travelers to Africa, it is not recommended to take it to prevent malaria, but to have a heavy dose with you for when you actually contract it (“drop a Lariam bomb”).

      • Aapje says:

        Supposedly, it is better to take malaria drugs in advance if the chance of infection is fairly high. So it would depend on where you go to.

      • SpeakLittle says:

        I took it during a trip overseas and experienced incredibly vivid dreams to the point that occasionally I had trouble distinguishing between dreaming and waking. I had one about a month after I stopped taking the medication but nothing beyond that. Someone else I know relayed that he had semi-hallucinogenic dreams as well, which stopped after he took it.

        Reading that article, I wonder if there weren’t more subtle or persistent side effects that I’m not aware of.

  20. Razorback says:

    From my own experience with 1p-LSD, about 20 average dose trips over a span of two years, I can say that one effect in particular seems to me like a permanent addition I didn’t have before. And that is the level of crispness and detail of my mind’s eye late at night while trying to fall asleep. I believe they are called hypnagogic hallucinations.

    I’m happy to have them. I wish I could visualize things in my head with such detail all the time.

  21. Dog says:

    My totally speculative theory on this has always been that some part of the brain’s perceptual system doesn’t have a strong tendency towards homeostasis (unlike e.g. the reward system), and that psychedelics can cause a re-weighting of these neural connections that never shifts back to normal. Long-term potentiation and depression are things that happen, right? Do they last longer in certain types of neurons / connections?

  22. vV_Vv says:

    The alternative is thinking of the body as a chaotic system which settles into various attractors. Take the wrong drug and you can push yourself into a different attractor state, which will persist until something shifts it. This definitely seems true of some things, and is one of the ways I think about depressive episodes – which can last months or years, and which can be precipitated by some sort of obvious stressor (getting fired, breaking up, being bullied) but last long after the stressor is gone. If this explains permanent drug side effects, it seems somehow scarier to me than the other option. It’s not just that you have to make sure not to accidentally kill any cells. It’s more that nobody has any idea what the underlying mechanisms look like, anything can happen, and you just have to hope you don’t screw up.

    This certainly makes sense by analogy with artificial neural networks: learning the weights of an ANN is a highly non-convex optimization problem, where you end up in a different local minimum depending on the weight initialization and the order in which the training examples are presented. Researchers have found, mainly by trial and error, randomized heuristics that find good local minima with high probability, but you can certainly screw the learning process by using a bad weight initialization, or presenting the examples in a bad order, using a bad learning rate schedule, etc, and if you then switch to good settings without restarting from the beginning, the learning process may or may not recover.

    The brain is different from an ANN and may not learn by gradient descent, but whatever learning algorithm it uses, the problem of optimizing the synaptic weights (and creating and pruning synapses) is still going to be highly non-convex, therefore it is quite likely that it is possible to send the brain into a bad local minima by putting it in an abnormal state even briefly. The most obvious example is probably PTSD, where even a single brief traumatic experience can cause life-lasting behavioral modifications, but it’s probably possible to achieve even greater alterations by affecting the brain chemistry.

    • Peter says:

      By some coincidence just today I was editing a paper talking about (among other things) where a neural network ends up (well, err, goes through, as we do some early stopping to avoid overfitting) based on where it started.

      There’s “transfer learning” where you train up a network on one task, then re-train bits of the network on another task, for eventual use on that other task. If you’re lucky (or good at picking your initial task) this lets your network find a better optimum to arrive at. If you’re not so lucky, it can send your network to a worse optimum – “negative transfer”.

      So, maybe: be careful what you learn, it could mess you up for being able to learn other things.

  23. Patrick Cruce says:

    If the guys that wrote these neuro studies were trying to analyze my computer, they’d say that graphical aliasing occurs because of an excess of 1 bits in my GPU.

    If it was caused by cell death, then we should also expect it to be a disease of aging and/or traumatic brain injury. Some people should just be unlucky enough to lose those critical cells by bad luck. (Unless these hypothesized cells are also immortal?)

    I’m surprised that learning and plasticity isn’t part of the explanation. If I have a great vacation or a traumatic experience and my behavior changes for the rest of my life, we just call it a “life changing experience” If I see a new face even just for one conversation, I might be able to recognize it years later. But if I don’t learn cantonese as a child, it is extraordinarily hard to learn to recognize the tones as an adult. If I’m congenitally blind from birth until age 25, it might take years to learn to see shapes.

    These observations, point to the idea that different functions have very different plasticity in adulthood. Primary sensory processing rarely changes. One hypothesis is that it is somehow, on rails, biologically. Neural factors that affect their ability to learn may not be expressed equally in different brain regions. Another is that the whole cortex may be equally plastic, but because primary sensory regions have very regularly structured input, they produce regular output.

    HPPD can be explained under either hypothesis.(or a combination) It may temporarily encourage the expression of learning factors that are typically not present in adults for these functions; causing some aberrant learning, that cannot be easily unlearned after the expression of these factors subsides. From a structured input perspective, a hallucinogen produces input endogenously and without the typical structure of the exogenous input. The same neural structures that allow rapid permanent learning for facial recognition or new behaviors were always present in these regions and can now take effect in the presence of this new stimulus pattern.

    Note that people often describe LSD as a life changing experience, in the same way that more common forms of permanent learning are often described. But maybe the learning is just a little broader.

    • Simon_Jester says:

      If the guys that wrote these neuro studies were trying to analyze my computer, they’d say that graphical aliasing occurs because of an excess of 1 bits in my GPU.

      If it was caused by cell death, then we should also expect it to be a disease of aging and/or traumatic brain injury. Some people should just be unlucky enough to lose those critical cells by bad luck. (Unless these hypothesized cells are also immortal?)

      I think your broader point about how this may be related to plasticity and the brain “learning” some potentially counterproductive quirks from its LSD experience is pretty good.

      But specifically looking at this, IF the “LSD kills some of the cells that regulate your sensory perceptions, potentially causing permanent under-regulation of perception” hypothesis is correct… Well, those cells would presumably be distributed throughout the brain or at least throughout the visual cortex.

      Traumatic brain injuries sufficient to wipe them out wouldn’t wipe out all of them unless they were extensive neough to destroy the whole visual cortex, in which case the victim won’t be hallucinating, they’ll be blind.

      Aging would tend to wipe out all types of brain cells at a roughly uniform rate. So again, by the time I’ve lost 40% of my regulatory system and am starting to hallucinate, I’ll have lost 30-50% of everything else and am effectively a vegetable.

      No, to get hallucinations caused by the death of ‘regulatory neurons’ or whatever we call them, we’d need some kind of highly specific cause that targeted the regulatory neurons in particular and went after them like a guided missile. Which is, to be fair, exactly the kind of thing that a specific chemical substance might do.

      • Patrick Cruce says:

        Let’s assume the hypothesis true: an undetectably small number of crucial regulatory neurons are killed by LSD. Since we don’t see HPPD as a side effect of brain trauma we must infer that they’re distributed as well.

        But cell loss is actually pretty high over a lifetime. This paper used tissue thickness as a proxy and found it declined from around 90 um to 30 um at 100 years. It is an open question why neural performance doesnt decline linearly. (it tends to plateau, then fall off a cliff)

        http://iovs.arvojournals.org/article.aspx?articleid=2125370

        See figure 1. I’m not suggesting HPPD should be a ubiquitous disease of aging, but why don’t we see it at least occasionally? Someone who gets unlucky in which cells are lost.

        The best extant model for targeted cell damage that I can think of is parkinsons. But
        (1) the critical regulatory cells exist in a specific region (substantia nigra)
        (2) Brain Trauma can create parkinsons (eg boxers)
        (3) Certain chemicals will target these cells preferentially. (MPTP)
        (4) It is a disease of aging.

        So if the LSD cell death hypothesis is correct it is a pretty unique brain malady.

  24. jplewicke says:

    I think that you can explain this with a combination of the predictive processing model and analogies to insight meditation. I think the resulting explanation also applies to the stages of insight meditation from Mastering the Core Teachings of the Buddha(MCTB) and stuff like Kundalini phenomena as well.

    So the basic predictive processing model says that there’s a process of reconciling different predictions between top-down predictions with bottom-up sense data. At first the top-down model just overrides the bottom-up sense data. Each time the bottom-up data is surprising, this releases some small amount of a neurotransmitter. Eventually some cumulative threshold is reached and the top-down processing neurons starts noticing that they’re encountering errors and surprising information. They start to try to adjust their output to try to accurately predict the bottom-up data, emitting some slightly different neurotransmitters in the process. Eventually a combination of the right neurotransmitters and developing a better model of the world through trial and error allow both the top-down and bottom-up models to come to a mutually agreeable and consistent view of the world, and the basic phenomenon isn’t surprising anymore.

    The basic premise of insight meditation is that most people’s top-down priors about their subjective experience of the world are incredibly wrong, in ways that are hard to understand until you’ve paid close enough attention to the details of your subjective experience. This includes stuff like believing that you’re a separate agent interacting with an objective reality, that objects continues to exist in your subjective experience even when you’re not thinking about them, and just generally that everything is way more solid and long-lasting than it actually is. Insight meditation or psychedelics are both methods for directly experiencing that that’s not true and changing your top-down and bottom-up models of the world.

    Insight meditation follows the basic predictive processing model of trying to reconcile erroneous top-down perceptions to noisy/surprising bottom-up sense data. The difference is that insight meditation involves huge swathes of the brain, and that it involves having hugely surprising and improbable experiences. That adds up to megadoses of neurotransmitters being released, with the exact mix of neurotransmitters depending on where the brain is at in the process of reconciling top-down versus bottom-up data. The experiences of insight meditators can thus have a common similarities in how they’re experiencing the world, since the sequence of neurotransmitter release and surprise-reconciliation strategies changes in a predictable basis. This is the basis for the Progress of Insight stages that Daniel Ingram writes about in MCTB. When it comes to the states in concentration meditation, I like Leigh Brasington’s article on the neural correlates of the jhanas, which are a set of commonly-experienced states in concentration meditation. I haven’t read Surfing Uncertainty, but I’d bet that there’s a lot of overlap in the neurotransmitter sequence from the predictive processing model and in Leigh Brasington’s sequence of neurotransmitter evolution. And there’s definitely an overlap between the insight stages and the concentration states — Daniel Ingram discusses a mapping of this in his chapter on the vipassanna jhanas.

    So what does all of this have to do with HPPD? Well, I beleive that predictive processing says that groups of neurons that consistently come up with surprising information get rewarded and listened. And insight meditation says that our priors about our subjective experience of the world are extremely wrong, and that the reality of what’s going on is extremely surprising. This difference between our current priors and reality means that any parts of our brain that know the right way to look have an abundance of things to point out as really surprising. And each time they point that out, they get rewarded with neurotransmitters and being listened to a little more carefully.

    Under normal insight meditation conditions where someone continues practicing and is doing so deliberately, this happens mainly from the viewpoint of the person who is meditating, and they feel like it’s under their conscious control. But in the case of HPPD there’s no reason it couldn’t be a rogue group of visual neurons deciding to continually point out visual snow, or to point out that their perception of the wall changes many times a second based on new neural pulses. And in the case of Kundalini phenomena, there’s no reason that the neurons behind a basic physiological drive like lust or hunger can’t suddenly say “Wow, if I pay attention to the impermanence of sensations in this insight-meditation-like way, then I can constantly reap the rewards of lots of dopamine.” I like Kevin Simler’s discussion of this in Neurons Gone Wild, from his excellent blog post series.

    • lydgate says:

      Thanks for this really insightful and interesting response.

      I also felt there might be some connection between permanent psychedelic states and the permanent experiential changes that arise from meditation. I wanted to point to Robin Carhart-Harris’ paper, which suggests that psychedelics reduce the activity of the Default Mode Network (DMN). Some of this is quite well-summarised in Michael Pollan’s new book, How to Change Your Mind, though the paper itself is well-worth reading. As I understand it, the argument is that this network also, in addition to its more familiar roles in ruminations about past and future, social cues and so on, controls something like “routing tables” for brain connections. The paper argues that conditions like depression, addiction, or eating disorders result from low-entropy (in other words, excessive rigidity of routing) in the brain. It also argues that children’s brains are not yet wired like this since the DMN forms relatively late in adulthood. The evidence suggests that psychedelics, through attenuation of the DMN, increases entropy in routing. I believe other studies have shown that meditation can also reduce DMN activity.

      If this is the case, then what Daniel Ingram is speaking about as enlightenment, liberation, awakening, etc, is a more-or-less stable reduction in DMN routing activity, resulting in less rigidity of pathways and therefore a higher tolerance for entropy in sensory experience. This would match both earlier states of evolution, since the DMN is evolutionarily recent, and also the state of childhood, since the DMN develops in adulthood. Accounts both from extremely advanced meditators, and from people on high dosages of psychedelics, often report not only a sense of “return to childhood” but also the “noetic” sense that William James described as characteristic of mystical experience—the sense that one is seeing revealed truth. In other words, maybe it feels like the truth because it is unmediated by the abstractions or shorthand of the DMN, just as experience was earlier in our lives and earlier in our evolutionary histories. The DMN is very useful in creating a sort of “autopilot” mode that is optimised to keep us alive with a minimal expenditure of brain effort; therefore when disabled, either by psychedelics or mindfulness/insight meditation, a sense of wonder arises. I don’t know enough to speculate about how, in technical terms, this would be made permanent, but it seems to me that it would relate to permanently reduced DMN activity and a resultant permanently increased state of entropy in the brain.

      I’ve read Brasington’s book on the jhanas and remember him describing them as magnetic, but I’d never seen that page on the neurological correlates, so thanks for that.

  25. dank says:

    Jean-Paul Sartre took Mescaline in 1929, after which he saw little crabs following him around for the next decade. https://www.nytimes.com/2009/11/15/weekinreview/15grist.html

    “Yeah, after I took mescaline, I started seeing crabs around me all the time. They followed me in the streets, into class. I got used to them. I would wake up in the morning and say, ‘Good morning, my little ones, how did you sleep?’ I would talk to them all the time. I would say, ‘OK, guys, we’re going to class now, so we have to be still and quiet,’ and they would be there, around my desk, absolutely still, until the bell rang.”

    I wonder how difficult it is for these studies to differentiate between ‘permanent’ vs ‘lasts 10-15 years’.

  26. ChuckleberryFinn says:

    Judging from the referenced review of TD, its proposed mechanisms are just as speculative as HPPD.

  27. nameless1 says:

    Months and sometimes years? I am pretty sure I was already depressed at around 13 and am still at 39. I would assume it is a lifelong thing, a personality thing.

    • Simon_Jester says:

      Some people have intense depressive episodes for relatively limited periods of time (months or years) that just go away on their own eventually. Based on what Scott’s said, this is the more common kind of clinical depression.

      Other people have permanent or near-permanent depression; this is also a documented thing Scott’s talked about- apparently it’s a somewhat different condition.

  28. Name hidden for obvious reasons says:

    I have some personal experience.

    Some years ago, I played with LSD about once a month, for about a year.

    I still have a long term effect, but I’m hesitant to describe it as a “hallucination”. When I’m somewhere with very bright light like noonday sun, or very low light like indoors at night with the main lights off, or for an hour or so after waking up each morning, or when I’m very tired, or I can also carefully relax and meditate myself into this state… I can tell that my brain is “faking up” most of what I “see” outside the tiny center of high resolution color vision in the middle of the field of view.

    This is true for everyone that your brain is faking most of what you see, including you, right now, you the person reading this text. But you are typically not aware of it.

    But me, now after maybe a couple too many acid trips, I can be aware of it. Text outside of my central vision is replaced by random characterlike garbage, unless I “know” what it is “supposed” to be, then it’s what it’s supposed to be. Which can be wrong, and I can see the text change from expected to reality when my central vision moves to it. Items and objects outside my central vision decay into lower resolution collections of colored planes, and then finally into “sketches” and then icons of what they are. And their precise location and precise relative locations will fill with errors, so they will then suddenly *move*, snap back to correctness, when I look back directly at them. If something enters my peripheral vision from the side, they are mostly just random jumbles of planes of non-saturated colors, until they enter my central vision, which can be slightly jarring if they had pattern matched to the wrong kind of object, because then they will suddenly transform into what they really are. If the something entering my peripheral vision from the side is a person, they are mostly just a low color contrast “cartoon”, like a low res CGI, until I look directly at them.

    On top of all this, when I’m very tired and the local light is a mostly point source, such as small LEDs on electronics in the area, I become aware of the blindspot in each eye, and the flickering reddish shadows of my retinal blood vessels as my eyes saccade. And sometimes even the jump-jump-jump flicking field of view from the saccades.

    I don’t have any fear or emotional reaction from any of this. If anything I get wry amusement, at becoming so aware of the physical truth of “we peer through a mirror, darkly”.

    I suppose that if I didn’t have an explanation of this perception based on knowledge of the frailties and evolutionary hacks in human perception, if I started with the assumption that there is nothing wrong with my vision, it must be the universe that is wrong, it could be a lot more upsetting.

    • Quixote says:

      I get many (but not all) of the same things, though stemming from meditation rather than drug use. I agree that if I didn’t have the scientific knowledge to know that this is more accurate rather than less accurate it would be pretty off-putting. Also, the fact that I can toggle it makes it not that practically annoying; when it would cause a problem it goes away.

    • Enkidum says:

      So… this is interesting. One reason why most people don’t notice that they only have high-resolution sensory input over roughly a 1° circle at the center of their visual field is because their eyes are constantly moving – about 2-6 times per second. So your high-resolution vision location is shifting, and so your model of different spatial locations gets updated fairly regularly.

      If you force someone to keep their eyes stable for long enough (or you maintain the same image on the retina by moving input based on eye movements), however, the edges of their visual field will begin to degrade (and eventually the entire scene will fade out, I believe, it’s been a while since I looked at those papers).

      So… I wonder if your effects could be cause by something as simple as having learning to keep your eyes really, really still for an unusual length of time. This is extremely difficult, but it might be responsible for what you’re talking about?

  29. dark orchid says:

    > somewhere someone got a consent form saying “we’re going to give you radioactive LSD” and thought “sure, why not?”

    I’m more surprised that somewhere in the world, there is apparently an IRB that signed this off.

  30. AdamOfCascadia says:

    HPPD reminds me a little of Mal de debarquement syndrome (https://en.wikipedia.org/wiki/Mal_de_debarquement), a condition usually triggered after the sufferer takes a cruise or flight. After disembarking, they continue to experience a rocking or swaying motion, permanently.

    This sounds a lot more similar to the chaotic system theory than the dead neurons theory, as no one seems to think that going on a flight will kill brain cells. Kind of shocking that one could be shifted into a new, very unpleasant attractor, just by motion!

  31. Garrett says:

    When you mention HPPD impacting some 1-4% of LSD users, I think it’s important to acknowledge not just the quantity of people, but the severity of the impact. Looking at The Wiki’s definitions, it includes things like halos and greater perception of things like floaters. I’ve never done any hallucinogen (to my knowledge) and I occasionally experience these, apparently to a slightly greater extent than the population at large. But these not be debilitating.

    It’s like pointing out that vaccines have a high risk of injection site soreness. No kidding. But it’s also pretty inconsequential in the grand scheme of things.

  32. PaulInMaryland says:

    You mentioned tardive dyskinesia, and I wanted to share my family’s experience. My mother-in-law received Reglan (metoclopramide), and got permanent TD – a tongue thrust. (The tongue thrust disappeared once or twice for a few minutes when she was extremely agitated.) TD is a well-known risk of Reglan. My wife received Reglan once for nausea, and a minor facial twitch started. Fortunately, it disappeared after half a day.

    These and other episodes lead me to believe that there is a genetic disposition to TD from Reglan.

    • LGood says:

      Metoclopramide is a dopamine (D2) antagonist so it will always carry the risk of TD. I was given it for severe vomiting about 20 years ago and developed rapid onset of suicidal ideation and uncontrollable sobbing. From normal mood to a nearly psychotic depression in 3 days. This resolved in another 3 days after I stopped the metoclopramide. Needless to say, I’m not a fan.

  33. HeelBearCub says:

    I’m biased in favor of killing-off-neurons hypotheses because they’re comfortable and they make sense. Of course if a drug kills something, it’s going to permanently impair function. This makes the idea of “drugs with permanent side effects” a little bit less scary, restores us to the “some medications cause strokes and then you’re screwed” realm of everyday life.

    This seems like discomfort with the idea that “you” aren’t really “you”, a desire for an immutable self.

    I suggest that a belief in, and a desire for, an immutable self is a source of some biases.

  34. P. George Stewart says:

    “It’s more that nobody has any idea what the underlying mechanisms look like, anything can happen, and you just have to hope you don’t screw up.”

    Hah, that’s just life for most people.

  35. Gerry Quinn says:

    Has ECT been tried with HPPD?

    Seems like it might be just the ticket for knocking out a stable attractor.

  36. behrangamini says:

    Two Explanations:
    1. HPPD not real. Your reference standard is people telling you “I’m hallucinating.” You have secondary and primary gain. People lie about their disease to their health professionals (on the level of making serious stuff up). Drug users (?correlation with anti-social traits and drug use?) lie to their health professionals at a higher rate than non-drug-users (also, didn’t someone come up with the lizardmen hypothesis for these sorts of things?)

    2. It’s real, but its relation to LSD is coincidence. Some people will develop long-lasting hallucinations without or with LSD. The types of people who will develop long-lasting hallucinations without LSD have the character traits that draw them to drugs society considers dangerous (e.g., LSD). A lot of them try LSD. Some get HPPD. LSD gets blamed.

    Example from my world: We’re super careful in giving iodinated contrast agents to patients with renal failure. Why? When people studied ICU patients with renal failure who got contrast-enhanced CTs, they noticed renal function got worse. Guess what? A lot of ICU patients with renal failure getting non-contrast CTs also had their renal function go down after the non-contrast CT. Why? ICU patients are sick, and they’ll have ups and downs in renal function.

    Combine bad reference standard (lying humans telling lies about how they feel for various reasons) and coincidence, and you have to consider very strongly that HPPD, like multiple personality disorder (or whatever the new name is), is not a real thing.

  37. MB says:

    The word “chaotic” seems uncalled for here, though admittedly it sounds cool. Maybe “dynamical system” is more appropriate.

    • Controls Freak says:

      I mean, calling something a “dynamical system” is about as bland a descriptor as possible. “Object in a universe that is not subject to Zeno’s paradox,” basically.

      That said, you’re right that maybe we don’t jump straight to chaotic. Other simple (non-chaotic) nonlinear systems can have multiple stable attractors, and you can have single forced trajectories that cause a jump from one to the other.

      (Honestly, I’ve really come to hate most dynamical systems terminologies/analogies applied to biological systems. Sure, they’re dynamical systems. They’re also complicated AF. Tons of different confusing perspectives. (E.g., when we look at animal sensorimotor behavior, it seems suuuper weird that a bunch of little highly nonlinear components are put together to make linear-looking overall systems all the time.) I’m really just getting fed up with extremely loose parallels that often don’t even work that well, much less shed any light on how we should really understand what’s going on in the biology.)

  38. outis says:

    I have a question about visual snow, as seen on the HPPD Wikipedia page. I have always seen visual snow on flat-colored surfaces, especially white ones. I remember noticing this when I was a child. Is this actually abnormal? Do most people perceive a flat white wall as uniform white, with no moving “noise” effect?

    • Simon_Jester says:

      I can vouch that at least some do, or that the ‘snow’ effect is so subtle as to be nearly imperceptible. What I DO perceive is those dark spots that represent flaws or flecks of matter in the eyeball, the ones that swirl and move when you try to focus on them because they’re inside the eye. However, that’s not the same as seeing crawling patterns of white.

      Do you perceive moving noise effects on nonwhite surfaces?

  39. onyomi says:

    This reminds me a bit of that phenomenon where some people can have a spinal mri with seemingly few serious problems and yet experience debilitating back pain, while others can have what appears to be terrible spinal problems show up on an mri and yet experience few, if any symptoms, and the related “I cured my back pain through journaling about how my mother didn’t love me” thing (associated primarily with Dr. John Sarno, I believe). It’s not that detectable, gross-level spinal problems don’t correlate with perceived back pain and disability, just not nearly as highly as one might expect.

    If it were possible to image e.g. the functioning of the serotonin receptors of a living person I would bet on encountering a similar phenomenon: people whose brains appear to be in bad shape nonetheless functioning happily and others whose brains appear totally fine crippled by depression, anxiety, panic, etc.

    If I’m right, both could be examples of “attractor” states where the mind-body gets into a reinforcing homeostasis of being in pain, depressed, etc. To go back to the back example, I think most back pain isn’t a direct result of spinal nerves actually signalling pain. It is instead a result of spinal nerves signalling back muscles to spasm and having muscles in a spasm state creates pain and dysfunction. This is probably adaptive right after the spine has suffered some kind of acute injury and it basically wants to freeze the surrounding muscles to allow itself to heal unmolested, but probably becomes habitual in the case of many chronic back pain sufferers, who, though their actual spine is in no worse shape than many people living without pain, may get stuck in an unfortunate oversensitized state. Journaling about their mother may provide the moment of introspection necessary to e.g. become consciously aware that they are tensing their back every time they feel stressed.

  40. Chainstate says:

    Ha, I’ve actually searched SSC in the past looking for mentions of HPPD – a bunch of Scott’s blogs kinda danced around the subject.
    I’ve had a form of HPPD for about 4 years now. Took a low doze of 25I-NBOMe, which is one of the nastier synthetic LSD knock-offs. No experience with psychedelics before or after, other than some minor experimentation with weed a year earlier. My trip was stressful (which seems to be a common – but not ubiquitous – trend with HPPD cases), but otherwise fairly unremarkable.
    A month later I began to notice traces following my hands in certain lighting, along with some secondary visual disturbances and a general sense of something not being right. That triggered a full-blown anxiety episode: I was so scared I could barely sleep, started to fast in order to “cleanse my system” (following some woo-y advice I dug up online), visited a crapload of doctors, went into therapy and almost dropped out of college. I developed secondary symptoms (some likely triggered by the neurosis), such as fasciculations across my whole body, tinnitus, CEVs. The hellish part was not being able to distinguish the legitimate visual disturbances from the normal visual function that I was just hyperfocused on.
    After a few months my initial tracers went away (I could no longer see a phantom hand trailing my own), but I developed something more like a conventional case of Palinopsia – prolonged afterimages, tracers on distant objects moving along a contrasted background (during the daylight), passing car lights leaving black lines in vision (during the night time). Reading became harder – I’d get persistent horizontal lines after staring at text for too long, which would usually trigger another anxiety episode.
    The first year was hellish, but eventually I just kinda accepted it, and little-by-little I stopped letting it interfere with my life. Finished my degree, switched to audiobooks, avoided driving at night. Nowadays, I barely think about it.
    An interesting thing about HPPD is that its symptoms have a sizable overlap with the Visual Snow Syndrome. Both are incredibly rare, but the main difference between them is just that the VSS cases aren’t triggered by drugs. Anecdotically, VSS also seems to have some kind of a genetic basis – a few VSS sufferers have relatives who experience it as well. VSS also seems to be linked to migraines in some vaguely defined way. I do wonder if my HPPD/Palinopsia has some genetic basis, too.

  41. Chebky says:

    Both the link here to the Cell paper and the Vice article it came from are for a structural paper describing the molecular detail of the LSD-SR complex, and I did not see any mention of radiolabeled pharmacokinetics in it. Is it the wrong paper or did I miss something?

    • Chebky says:

      Also, you mentioned a few times about papers that are behind a paywall that you can’t access. I’m sure I’m not the only one here but I can access almost every exact science/life science/medical journal you might need, so (anyone here) can feel free to email me a link to chebky (in gmail) and when I’m in the office (or within the institute wifi) I’ll try to get it.

    • Slava Bernat says:

      Just wanted to second that.
      The study is great and super high quality but it didn’t require anyone to give consent to be injected with radioactive LSD, not even an animal.

  42. Bram Cohen says:

    My guess is that it has to do with increased brain interconnectivity. Many people describe LSD as making permanent changes in their brain, usually in a positive direction: Vision being more three dimensional, their emotions being more accessible. One fascinating thing I noticed on LSD was that I could ‘see’ the grammar of everything everybody said in fine detail, a type of parsing I had previously simply used as a black box, and even after coming down I still had the ability to think about grammar in that way and was able to improve it over time where previously I hadn’t even had a starting point.

    Brain interconnectedness is not a straightforwardly good or bad thing. It’s a parameter which has tradeoffs at different values. My brain happens to have very little ability to imagine visually. Other people are on a spectrum from where I am, to being able to imagine, to vividly imagining, to seeing things which they can easily differentiate from hallucination by thinking about it, to having visuals which they can tell aren’t real but sufficiently intense that they obfuscate what’s actually being seen a bit, to having full on, can’t tell they aren’t real visual hallucinations. I’ve spoken to people about their subjective experience of the world and a surprising number of people are just below the top level of that and simply view that as normal perception. Maybe on most people LSD bumps up their imagination a bit, but people who already were a bit close to the top get bumped from vivid imagination into outright hallucination.

    Likewise for people who persistently hear voices after an acid trip. Maybe the voices were always there in the person’s brain, but it wasn’t until doing the drug that they learned the ‘skill’ of ‘hearing’ the voices, and once you’ve learned that skill you can’t un-learn it, any more than you can un-learn the ability to whistle.

  43. Upthorn says:

    I don’t understand why there should be such an extreme emotional gulf between the idea that “some medications cause strokes and then you’re screwed” (a specified outcome with an unspecified mechanism) vs “the body [is] a chaotic system which settles into various attractors. Take the wrong drug and you can push yourself into a different attractor state.” (a specific mechanism with a nonspecific outcome.)

    What if the reason that some medications cause strokes and then you’re screwed is because the body is a chaotic system which settles into various attractors, and taking the wrong drug at the wrong time can push you into a different attractor state, which leads to a feedback loop cutting off blood circulation to an area of the brain. This is why they only sometimes cause strokes, and why it’s basically impossible to predict whether a given administration will cause such a stroke.

    If “the body is a chaotic system…” winds up being the underlying cause for every medication side effect, and the distribution thereof, it doesn’t change the state of affairs any, it just provides some level of direction to any medical institution who might want to research into screening tests to prevent accidentally giving their patients a stroke, or HPPD, or TD…

    • Simon_Jester says:

      Because “the body is a chaotic system…” isn’t the underlying cause for every medication side effect, only some of them.

      A lot of side effects are caused by deterministic processes that are, to borrow a term from Seeing Like A State, “legible.” That is to say, it’s easy to come in from a top-down perspective and say no, people with low platelet count shouldn’t take this medication, because it frequently impairs blood clotting, and getting a double dose of ‘blood won’t clot well’ is very bad for you. But if you do start taking it, and then stop, your blood will start clotting as well as it did before you took the stuff. Unless you’ve been specifically damaged in a measurable, clearly apparent way by the side effect, the body restores homeostasis.

      Stuff like this is easy to comprehend, and if you’re a high-conscientiousness, causality-oriented psychiatrist, it’s a relatively comfortable mental universe to occupy. If all side effects are directly explicable by “this medication does this obviously bad thing in these patients,” and they go away if you stop taking the stuff, then medicine is ‘legible’ and all is well with the world.

      But what if there are whole categories of side effects wherein all the parts of the body are functioning just fine, nothing has been damaged or made dysfunctional in a measurable way, and yet the patient is in constant agony or screaming about the hairy purple spiders crawling all over them? And where, having taken away the medication, despite nothing being obviously wrong, the patient is still in agony and/or has hallucinatory spiders all over them? Homeostasis doesn’t come back, the patient is apparently damaged, but how?

      This is a very different order of problem, and much scarier. Because one of the core assumptions of medicine is that most things will heal if you can address the root causes of a disease and repair any organic damage to the body, the body will get better.

      Here, the root cause (a medicine that knocked you into a new attractor state) has been removed, and there’s no apparent organic damage to the body, but the body just… doesn’t heal,

      O_o

  44. Cardboard Vulcan says:

    One similar process that might suggest a similar etiology is the phenomenon of kindling of seizures. A substance that induces a seizure will sensitize to subsequent seizures such that a lower dose is required to produce a seizure, or in some cases seizures may then occur spontaneously. I am not suggesting that HPPD is a form of seizure, but that there may be some similarity in that repeated stimuli may sensitize the brain in some way.

    The observation that anticonvulsants including levetiracetam, lamotrigine and others are effective in HPPD would seem to support this idea.

    There is also a similar process that affects heart arrhythmias such as atrial fibrillation in which one episode seems to sensitize to later episodes.

  45. herbert herberson says:

    Speaking as someone who has experienced very minor forms of it (albeit not for some years), and has friends who have as well, I very strongly believe it is essentially learned. In taking acid, you learn to see things in certain ways (physically, this probably takes the form of new neural connections), and to some degree those lessons can stay with you.

  46. fr8train_ssc says:

    Interesting observations on several of the posters explaining how they felt HPPD was “learned”. Apparently there was a study done 2 years ago looking at LSD’s affect on the Hippocampus and correlations between increased disassociation with diminished activity there. Maybe LSD somehow causes interference with involuntary memory, it would be interesting to see if there’s a correlation with the level of disassociation someone with HPPD feels or had felt during trips compared to the general population of LSD users that don’t develop HPPD.

  47. m1el says:

    > a theory where LSD kills an undetectably small number of very important neurons

    What if it’s the opposite? What if LSD reinforces certain neuron connections instead of killing neurons?

  48. blumenko says:

    Shouldn’t there be a way around gated papers for someone with as much influence as Scott, such as friends with access credentials, free pirating websites, or just paying using Patreon money?

  49. David Shaffer says:

    It’s well known that there are events that can knock someone into a different attractor state. Scott writes about patients who got depressed as the result of a stressful event, and then stayed that way once the stressor was removed. If, say, a divorce can do that, it seems to be expected that something like LSD could as well. So unless stress kills a tiny but crucial neuron population (definitely not impossible, but the priors are lower than for a psychoactive chemical), there’s no reason to think that attractor theory is wrong. Scary sure, but likely correct. Also, is it any scarier than “some things will kill parts of your brain, leaving you permanently damaged?” At least if this is an attractor shift, one might be able to get out of it.

  50. mupetblast says:

    OT but Scott has a mention in the print pages of the WSJ: https://twitter.com/WilcoxNMP/status/1005067097632845828

  51. Jotto999 says:

    I have experienced some version of this. For a long time I couldn’t even talk about it, because the subject was strongly associated with the anguish that I had ruined my own mind.

    On two occasions, I took one dry gram of mushrooms. That’s all. I know that I must be unusual in my reaction to it, given how HPPD is not associated with mushrooms as much as with LSD, and especially not at such modest usage. I tried weed a few times in highschool, and never did it again. Other than that, no illicit drug use in my history.

    I never experienced breathing walls or anything like that. What I would see is a bit hard to describe, but the best analogy is this: imagine if all your life, you have only ever seen motion at exactly 30 frames per second. Then suddenly, the framerate spontaneously becomes 90 frames per second, and the motion looks super smooth – to an extent that even looks weird or “wrong”, somehow. In these little episodes, this higher framerate effect would appear through my entire vision, such that any moving object would appear oddly fluid in its motion, even me waving my own arm.

    I gradually learned that this was the onset of a panic attack. It was strongly associated with the fear that my mind had been damaged, and that dementia is written in my future (a deep concern that I carry to this day, partly for other reasons though, such as that concussion I had when I was five years old).

    Another effect was that I was terrified of mirrors, and for a few weeks I had trouble going into the bathroom for this reason. I did gaze into a mirror for several minutes while on the mushrooms, which might have burned this into me. All of these effects did not start happening until a few months after I had done the mushrooms, which I always found a bit odd, and suggestive that it wasn’t the compound physically damaging me, so much as an already-present proneness to anxiety being exacerbated by the mushrooms. I could be mistaken about this, naturally.

    There is good news. I haven’t done any psychedelics for a couple of years. And the panic attacks/visuals have been happening less and less frequently over time. At this point, I am ready to start talking about it (for a long time, merely thinking about it would invite the onset). Nowadays I go weeks at a time without even remembering or having it at all, and they have become milder over time as well, often barely noticeable. And the amount of panic that I caused myself by reading other people’s comments and typing this one out has been pretty minimal and short-lived.

    Mindfulness meditation helped enormously, even just doing it for five minutes a day made a noticeable difference. EDIT: One other thing which unambiguously helped was to quit all caffeine, though I have found that as I recover I am able to handle it again without panicking.

    I am pleased to have typed this, and it feels like a milestone in my recovery. I would say that I am mostly recovered, and aside from occasional small panick attacks, I usually feel well. I plan not to touch psychedelics again, given that I probably have a special vulnerability to them. I notice that others in my family are prone to anxiety – perhaps it is in my genes.

    By the way, I’m not sure if you’ll read this Scott, but this website has been enlightening to read, and I feel fortunate to have access to such a mind as yours.

  52. avturchin says:

    I think and maybe even read somewhere that long-term LSD effects are connected with induced neurogenesis, which creates unwanted connections between visual neurons, which produces TV-snow affects and other distortions. Hebbian learning may play a role here, as the brain learns how to hallucinate and hardwires this type of behaviour.

  53. noaydi says:

    I thought about this alternative theory in the days I used LSD. I spoke about it to a friend another way (far less detailled than you), and he related actually himself to it by saying “I actually like that” (understand : like this process – he was taking drugs, changing his thought “phase” for long time, then it was re-changed with another particular use of the drug, ect.). I don’t know if this perception is very valid thought.

    There is something that I don’t get in yours last position thought : you seem to think the first way of viewing thing preferable compared to the second, but I would think it’s the contrary.

    There is actually no way to repair killed neurons, or marginal way wich still imply modification from original functionning (neuroplasticity, etc). In all, if it work like that, it is actually worse for current HPPD ppl but you seem to identify the value of knowing that mainly in preventive way : it’s as if we was based on the rule “if I know everything, nothing will happen to myself”.

    If we function like your theory speak about, the only problem is more like, we would have hard time determining our original state. The notion of “good” state would be only a kind of equlibrium. But it don’t prevent a possible resolution of symptom.