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Is Pharma Research Worse Than Chance?

[Epistemic status: very speculative]

The two most exciting developments in psychopharmacology in the 21st century so far have been ketamine for depression and MDMA for PTSD.

Unlike other antidepressants, which work intermittently over a space of weeks, ketamine can cause near-instant remission of depression with a single infusion – which lasts a week or two and can be repeated if needed. Ketamine use may be successful in 50-70% of patients who have failed treatment with conventional antidepressants. Ketamine treatment has some issues right now, but the race is on to create an oral non-hallucinogenic version which could be the next big blockbuster drug and revolutionize depression treatment.

MDMA (“Ecstasy”) is undergoing FDA Phase 3 clinical trials as a treatment for PTSD. Preliminary research has been small and underpowered, but suggests response rates up to 80% and effect sizes greater than 1 in this otherwise-hard-to-treat condition. None of this is on really firm footing – that’ll have to wait for the Phase 3. But signs are looking very good.

I say these are the two most exciting developments mostly because no other developments have been exciting. In terms of normal psychiatric drugs, the best that the 21st century has given us has probably been pimavanserin and aripiprazole, modest updates to the standard atypical antipsychotic model. These drugs are probably a bit better than existing ones for the people who need them (especially pimavenserin for psychosis in Parkinson’s) but they don’t revolutionize the treatment of any condition and nobody ever claimed that they did. And most drugs aren’t even at this level – they’re new members of well-worn classes with slightly different side effect profiles. The landscape was so quiet that ketamine came in like a bolt from the blue, and MDMA is set to do the same in a couple of years when the trial results come out.

(if I’m wrong, and history decides these two drugs weren’t the biggest developments, the most likely failure mode is that psilocybin turned out to be more important than MDMA)

There’s a morality tale to be told here about how the War on Drugs choked off vital research on some of the most powerful psychiatric compounds and cost us fifty years in exploring these effects and treating patients. I agree with this morality tale as far as it goes, but I also think there’s another, broader morality tale beneath it.

Suppose that neither ketamine nor MDMA were illegal drugs. Ketamine was just used as an anaesthetic. MDMA was just used as a chemical intermediate in producing haemostatic drugs, its original purpose. Now the story is that, fifty years later, we learn that this anaesthetic and this haemostatic turn out to have incredibly powerful psychiatric effects. What’s our narrative now?

For me it’s about the weird inability of intentional psychopharmaceutical research to discover anything as good as things random druggies use to get high.

For decades, pharmaceutical companies have been coming out with relatively lackluster mental health offerings – aripiprazole, pimavanserin, and all the rest. And when asked why, they answer that mental health is hard, the brain is the most complicated organ in the known universe, we shouldn’t expect there to be great cures with few side effects for psychiatric diseases, and if there were we certainly shouldn’t expect them to be easy to find.

And this would make sense except in the context of ketamine and MDMA. Here are some random chemicals that affect the brain in some random way, which people were using mostly because they felt good at raves, and huh, they seem to treat psychiatric diseases much better than anything produced by some of the smartest people in the world working for decades on ways to treat psychiatric diseases. Why should that be?

One could argue it’s all about numbers vs. base rates. There are way more chemicals synthesized each year by people who aren’t looking for psychiatric drugs than by people who are. Even if the people who are looking for drugs are a thousand times more likely to find them, the people-who-aren’t-looking can still overwhelm them with sheer numerical advantage. And maybe when a psychiatric drug is discovered by people who weren’t looking for it, what this looks like is a few random people trying it, noticing it feels good, and turning it into a drug of abuse.

And I’m sure this is part of the story. But that just passes the buck to the next question. Abusers take the vast flood of possible chemicals and select the ones they think will feel good at raves. Psychopharmacologists take the vast flood of possible chemicals and select the ones they think will treat mental illnesses. How come the abusers’ selection process is better at picking out promising mental health treatments?

Here’s one hypothesis: at the highest level, the brain doesn’t have that many variables to affect, or all the variables are connected. If you smack the brain really really hard in some direction or other, you will probably treat some psychiatric disease. Drugs of abuse are ones that smack the brain really hard in some direction or other. They do something. So find the psychiatric illness that’s treated by smacking the brain in that direction, and you’re good.

(in fact, the most effective existing treatment for depression is electroconvulsive therapy – ie giving the brain a big electric shock. This is maybe the crudest, most literally “smack the brain really hard” treatment out there, but it sure does work)

Actual carefully-researched psychiatric drugs are exquisitely selected for having few side effects. The goal is something like an SSRI – mild stomach discomfort, some problems having sex, but overall you can be on them forever and barely notice their existence. In the grand scheme of things their side effects are tiny – in most placebo-controlled studies, people have a really hard time telling whether they’re in the experimental or the placebo group.

Nobody has a hard time telling whether they’re in the experimental or placebo group of a trial of high-dose MDMA. I think this might be the difference. If you go for large effects – even if you don’t really care what direction the effect is in – you’ll get them. And if you go for small, barely perceptible effects, then you’ll get those too. The dream of the magic bullet – the drug that treats exactly what it’s supposed to treat but otherwise has no effect at all on you – is just a dream. The closest you can come is something with miniscule side effects but a barely-less-miniscule treatment effect.

But given that we’re all very excited to learn about ketamine and MDMA, and given that if their original promise survives further testing we will consider them great discoveries (and given that ECT was also a great and productive discovery) it suggests we chose the wrong part of the tradeoff curve. Or at least it suggests a different way of framing that tradeoff curve. A drug that makes you feel extreme side effects for a few hours – but also has very strong and lasting treatment effects – is better than a drug with few side effects and weaker treatment effects. That suggests a new direction pharmaceutical companies might take: look for the chemicals that have the strongest and wackiest effects on the human mind. Then see if any of them also treat some disease.

I think this is impossible with current incentives. There’s too little risk-tolerance at every stage in the system. But if everyone rallied around the idea, it might be that trying the top hundred craziest things Alexander Shulgin dreamed up on whatever your rat model is would be orders of magnitude more productive than whatever people are doing now.

Or it might not be. I can also think of a counterargument to the theory above, which is that our current best model of ketamine suggests it’s a non-psychoactive metabolite that has most of the useful antidepressant effect. In fact, a lot of people think that one form of ketamine is hallucinogenic (and extremely effective against chronic pain) and another form (or its metabolite) is the antidepressant. I’m a little suspicious trying to calculate the odds of a single chemical having two forms, one of which is a really exciting analgesic, and the other of which is a really exciting antidepressant, by two different mechanisms. It sounds too much like finding some new chemical compound whose solid form is a room-temperature superconductor, and whose liquid form catalyzes cold fusion, by two totally different mechanisms. It seems a little too lucky (see here for some ketamine skepticism, and here for my response). But if it were true, it means that ketamine’s psychoactive effects were a red herring in helping us discover it as an antidepressant, even though they were a very effective red herring.

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169 Responses to Is Pharma Research Worse Than Chance?

  1. gwern says:

    Another version of this would be the screener’s dilemma: what ketamine, MDMA, and psilocybin all have in common is that their ‘screening’, as it were, was done in humans; and humans are the very best model organism for humans. “When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis”, Scannell & Bosley 2016 points out that when doing a pipeline of substances, even small losses in predictive power can require huge numbers of samples to make up for, because you lose all of the good candidates early on. (Application to IQ/psychology/science left as an exercise for the reader.) The pharma industry, however, has moved decisively away from human screening or animal screening in favor of much heavier throughput in computer or molecular screening…

    So, what is the one thing that leaps out when you read about chemistry and drug development pre-1960s, and the psychedelics/‘research chemical’ scene? At least for me, what leaps out from the discovery of LSD, amphetamines and other drugs is the extent to which they were discovered by chance by chemists and researchers and patients and cats and dogs and mice ingesting them deliberately or accidentally and going ‘well, this isn’t curing my asthma too well but I sure do feel less depressed’ (amphetamines) or the pharma company handing out free samples everywhere and hoping one of the doctors will tell them what it’s good for (amphetamines, LSD). Or the psychedelics community with people like Shulgin setting out to just sample hundreds of novel chemicals just to see what they do, and the RC community endlessly experimenting with slight variations on known chemicals. No chemical assay will ever tell you ‘I feel less depressed after overdosing on substance X’ and make you start wondering if there is something there. While it’s horrifying to read something like Gergel’s Excuse Me Sir, Would You like to Buy A Kilo of Isopropyl Bromide (and note how everyone appears to get cancer quite young or otherwise die peculiarly), damn if they didn’t get results!

    • Jacob says:

      >For me it’s about the weird inability of intentional psychopharmaceutical research to discover anything as good as things random druggies use to get high.

      Scott and many commenters seem to be dancing around this point but I want to make something explicit: Lots of people were harmed as a result of “experimenting” with these drugs. People who take lots of new drugs with unknown effects often experience extremely unpleasant side-effects, up to and including death. The pharma industry is extremely averse to all side effects, especially death, which is why so many drugs spend so much time in animal testing before they get to humans. And often fail in human trials because of “toxicity” (aka unacceptable side effects).

      Now we don’t know how many people have died by taking home-cooked drugs, but a full risk/cost/benefit calculation would surely take that into consideration. It’s easy to think of something as a great idea by only looking at the success stories, which in this case are MDMA and ketamine[0], but those were chosen by a brutal selection process of human experimentation. Maybe druggies only look more “successful” because we have ignored the failures. It’s impossible to know how many people died from a drug humanity had never heard of before or since.

      [0] Since they’re in Phase 3 trials they’re more like “high probability of success” stories and may yet prove fruitless, but we can ignore that for now.

      • gwern says:

        Now we don’t know how many people have died by taking home-cooked drugs, but a full risk/cost/benefit calculation would surely take that into consideration.

        To make it more explicit:

        A RC guinea pig or a researcher sampling drugs risks only a few lives. The successful drugs and vaccines and surgeries which are the outcome of self-experimentation (and there are many of these) get used on literally millions and billions of people and going up every year indefinitely. Given the outsized long-term benefits of medical research (since ketamine has come up, I will simply note that depression alone costs millions of QALYs globally every year), the optimal cost-benefit is not going to miraculously, like a hundred coins flipped and all landing on edge, be 0 people dying in experiments or pilot trials (or anywhere near 0). We need many more people dying by taking home-cooked drugs and serendipitously discovering additional effects, many more animals cruelly used in animal research, many more randomized trials, and the failure to do so and the clamping down on research is very much a case of ‘the seen and the unseen’.

        • vV_Vv says:

          We do what we must
          because we can.
          For the good of all of us.
          Except the ones who are dead.

          This may make perfectly sense if you are an utilitarian, but most people aren’t.

          • This may make perfectly sense if you are an utilitarian, but most people aren’t.

            On the other hand, if you are a libertarian, you distinguish between people dying because of the choice of other people to experiment on them and people dying because of their choice to accept a risk in exchange for what they saw as a benefit.

          • vV_Vv says:

            The catch is that we are talking about mentally ill people, who may not considered to be fully competent.

          • notpeerreviewed says:

            Depends quite a bit on the mental illness in question. I’d say most depressives and PTSD sufferers count as fully competent. Paranoid schizophrenics, maybe not so much.

          • vV_Vv says:

            Depends quite a bit on the mental illness in question. I’d say most depressives and PTSD sufferers count as fully competent.

            Clinical depression is the main risk factor for self-harm and suicide. And attempting suicide is considered evidence of incompetence (rightfully? This is a difficult question.)

            So suppose you go to a depressed and quite possibly suicidal person and tell them: “Hey, do you want to try this drug? It may cure your depression, or it may kill you.”

            Can you see the problem here?

          • baconbacon says:

            So suppose you go to a depressed and quite possibly suicidal person and tell them: “Hey, do you want to try this drug? It may cure your depression, or it may kill you.”

            Sounds like a free roll.

          • gettin_schwifty says:

            As a depressed person, I’d love some ketamine. Certainly there are negative effects, but fixing depression makes all other goals much more reachable, which seems worth it. The legality is, of course, an issue.

        • wintermute92 says:

          get used on literally millions and billions of people and going up every year indefinitely

          If anything, I think the argument against human experimentation wouldn’t be negative utility but an accusation of Pascal’s Mugging. One-time costs pitted against indefinite-time payoffs are almost always worthwhile, even when the one time cost is enormous. The only upper bound on the utility of a new medicine is when it becomes irrelevant (most likely via the discovery of a better drug, more imaginatively via some advance that renders the disease irrelevant).

          I think in this case it’s not a mugging, though. The cost is relatively low, the people paying it are volunteers, and many of them aren’t even doing it as sacrifice for the good of man but because they enjoy the experimentation. I honestly have trouble believing that more experimenting with Shuglin’s compounds could be a bad decision overall.

          • gwern says:

            It’s not a mugging because you would discount future medical benefits which gives a large but finite value (even if you imagined a drug which cured everyone of everything), so there are no infinities at play, and it’s doubly not a mugging because all of these values can be measured and often have been (eg Global Burden of Disease).

          • baconbacon says:

            I always interpreted the mugging part being ignoring possible costs, such as angering a god for believing in the wrong god/believing for the wrong reasons and being thrown into an eternity of suffering for your imprudence.

      • random.name.0815 says:

        Scott and many commenters seem to be dancing around this point but I want to make something explicit: Lots of people were harmed as a result of “experimenting” with these drugs. People who take lots of new drugs with unknown effects often experience extremely unpleasant side-effects, up to and including death.

        Yet, the compounds mentioned specifically in the article, ketamine and MDMA are a long way from new. Ketamine has been around in clinical settings for decades, listed on the WHO list of 50 essential drugs and depending on where you are on the globe it is still a go-to anaethesic for the weakest (infants and the elderly) in many countries. Or at least it was about 5 years ago, maybe something has replaced it. I doubt it though. Ketamine is not just the horse tranquilizer media makes it out to be.

        MDMA has been around since at least the early 80s, first in the US homosexual scene, long before it became the go-to energy source for electronic music afficionados, so not exactly new either. On the other hand, lots of people have been “harmed” by prescribed antidepressants in one way or another – loss of libido that persists after tapering out the medication, really ugly withdrawal effects (venlafaxin, looking at you there…). Generally, the FDA mandated test and studies will only prove that the stuff does not kill you outright, that it will not slowly destroy your liver or intestine or skyrocket your blood pressure. If you clear those obstacles and have numbers that suggest an effectivity that is just a hairs width above placebo/control group you’re good to go to market. The true trial these days happens in the first years of prescription. The beta test customer.

    • Maxander says:

      Dang, I went and made an account specifically to post that precise paper, but I was only two days late…

      We might find, in the end, that drug prohibition policies are a long-term benefit for medical development. Most recreational drug users, if they could just do weed and acid in peace, would; they wouldn’t need to experiment with mysterious chemicals that hadn’t yet been made illegal. Legal pressures have caused black-market chemists to come up with all sorts of toxic things no one in their right minds would otherwise touch- bath salts, ‘synthetic marijuana’, and so on. They’re terrible things for unsuspecting humans to put in their bodies, but the ones that stick around are clearly doing something– maybe, someday, someone will come back and work out a useful therapeutic dose for some of them.

      • random.name.0815 says:

        While I agree, I feel it is worthwhile to point out that the “synthetic marijuana”-type drugs are a problem that stems not from the drugdealers greed, but from the greed of the pharm companies. At least the first and second wave of synthetics in that realm consists of “diverted” experimental drugs out of science / pharm loop. They are trying to “build a better mousetrap”, that is harness the qualities of cannabis while at the same time cutting out psychoactivity and of course the patenting issue.

    • Reasoner says:

      note how everyone appears to get cancer quite young

      What’s the easiest way to tell if something gives you cancer, short of administering it to people and seeing if they get cancer quite young? How do I evaluate something like this as it applies to the famous uridine stack, say? (You can pirate the full paper on scimag, quote from paper: “The study results presented herein changed the paradigm of uridine safety. Uridine homeostatic disorder is carcinogenic, and the pharmacological use of uridine may have far-reaching detrimental effects. Thus, the safety of pharmacological uridine may need to be reevaluated.”)

    • gwern says:

      Oh, and also AIDS. Would the antiretrovirals and combo-therapies been developed nearly as fast as they were if the American gay community had not devoted considerable resources to it and, critically, experimented on themselves like crazy? Mike Darwin says no: http://chronopause.com/chronopause.com/index.php/2011/05/31/going-going-gone-part-3/index.html Contrast the boondoggle of the Ebola vaccine with concerns over ‘imperialism’ barring randomized trials.

  2. Douglas Knight says:

    Although MDMA has several effects, surely the relevant one is that it is a psychedelic, a category that people shy away from, but which has been promising for decades.

    But the ketamine story is weirder. Why did recreational users settle on this particular sedative? Because it was easily diverted? That’s not selecting for interesting drugs. Ketamine replaced PCP in legal uses. Would recreational users prefer PCP?

    • Janet says:

      Ketamine is a legal drug (schedule III). It’s perfectly OK for a legal pharma plant (overseas or not) to make it, sell it, ship it– and, surprise, that Internet pharmacy turns out to be diverting some/all of it to the recreational drug market? Gosh, couldn’t know that! And dirty doctors can run “plastic surgery” or “pain” clinics and get it through legitimate channels.

      Also, that means that druggies can break into places and get it– it’s widely used by vets and animal control organizations, so you don’t even have to take the risk of busting open a pharmacy. (I worked for a vet in high school, and we were hit twice by druggies while I worked there– stealing antibiotics and anesthetics. Caught on the third attempt, by the new-and-improved security system, but still.)

      So, ketamine has plenty of practical benefits, due to its legal status, that PCP doesn’t. Druggies are simple people, for the most part; they’ll use the easy way if it’s available.

      • herbert herberson says:

        I’m in my early thirties, and I have a childhood recollection of my mom (who was trained as a vet tech and did pro-bono cat neutering for the neighborhood) complaining about how she suddenly couldn’t get ketamine anymore because people were using it to get high.

        So, less than 25 years ago you could order it from a catalogue even if you were neither a vet or someone who worked for a vet.

  3. DDDD says:

    So, what should people who are currently suffering from SSRI-resistant depression do?

    • Scott Alexander says:

      Things to try in order: augment with SAMe, switch to SNRI, switch to clomipramine/MAOI, try ECT. Maybe TCMS somewhere in there, I don’t know enough about it to have a strong opinion.

      (this is not official medical advice; talk to your doctor before doing anything)

      • Type1civilian says:

        Is it possible to detect a Levomefolic acid deficiency in a blood test? I take deplin because of an MTHFR gene mutation and it seems to work. The genetic test was expensive and my psychiatrist is offering more tests to see of there are other supplements I could be taking.

      • cuke says:

        Scott, do you see psychiatrists where you are recommending Deplin, or other L-methylfolate products, to augment SSRIs? I’ve seen dramatic results with a few people on this who were non-responders to SSRIs. (I’m not a prescriber, so this is as a non-prescribing psychotherapist witnessing effects in clients).

        I read some years ago that L-methylfolate is used as a first-line treatment in some countries in Europe and I know of a few US psychiatrists who swear by it, but most of the clients I’ve talked to who also see psychiatrists report that their psychiatrists have never heard of it, even as trade name Deplin. I’ve been a bit mystified about why it’s not more widely known or tried.

        TCMS, from the little I’ve learned about it, seems like a good thing to try because it’s less invasive than ECT (and without the potential memory loss) and where I am at least, some of the providers of it take Medicare for it. I don’t know about private insurance.

        • Douglas Knight says:

          To answer a different question, “Has Scott written about L-methylfolate?” yes, in three psychiatric articles, here, here, and here, and a broader article. (via google)

          The second article says that he wishes it were used more, so probably the answer is no, he does not see people using it.

        • Type1civilian says:

          I don’t know what Scott has to say, but in my case I needed a genetic test before the treatment was offered. I’ve been quite skeptical of it’s efficacy because there seems to be a lot pseudoscientific interest in this gene mutation and there’s even been a post about it on Science Based Medicine this is partly why I’m wary of getting more genetic tests. But I recently tried to stop taking Deplin (I no longer take SSRI’s), and it had been so long since I had been depressed that when I started experiencing symptoms it took me several days of not being functional for me realize that I was in fact, depressed. I find this frustrating because my psychiatrist isn’t very rigorous and wanted her to be wrong. In any case, I plan on a waiting a few years for the price of whole genome sequencing to go down.

    • J says:

      Scott’s things that sometimes help if you’re depressed is a much better answer to that question. In particular he gives quite a few important caveats about ketamine. (I was considering writing a top level comment noting the difference and wondering if he might want to put a little more boilerplate warning on this post).

    • Alkatyn says:

      Are there any countries where Ketamine is currently legal? Could take a holiday

      • Janet says:

        Ketamine is a schedule III drug in the US– it is used, both by physicians and veterinarians, as an anesthetic. It’s on WHO’s “list of essential medicines” and is available both under brand name (Ketalar) and generic. (That’s why these studies can be done at all– physicians can prescribe the drug off-label.)

      • cuke says:

        There are ketamine infusion clinics in lots of big cities in the U.S. now. There doesn’t seem to be any insurance coverage for it yet and it’s expensive (ballpark $3,000 for several treatments). But you don’t have to wait if you are in the U.S. and you have money to spend.

    • jes5199 says:

      Anecdotally, I tried Ketamine, and it seemed to help for a couple weeks.

      There is also Wellbutrin, which is widely prescribed, and has a different mechanism than SSRIs.

      • cuke says:

        Wellbutrin got a bad rap for causing seizures in some people I believe, but reporting later suggested that concern was overblown. It doesn’t tend to have the weight gain or sexual side effects of the SSRIs. I gather some folks get extra libido with Wellbutrin (and it’s maybe used recreationally in some countries?). Under brand name Zyban the same product helps with smoking cessation. My husband took it for that and said it removed the physical craving for cigarettes so he had energy to deal with the psychological addiction (still not smoking 20 years later).

        Wellbutrin seems to be a bit activating for some people, so I’ve heard it’s less good for people who also have anxiety, but maybe Scott could weigh in on that.

        I’ve heard of some pretty bad reactions in people who were taking one of the generics (Teva, bupropion) and when I asked a colleague who is a psychiatrist about it he said that he thought the generic may metabolize somewhat differently (because of different inactive ingredients? I don’t understand that).

        I don’t know why Wellbutrin is not a first-line drug over things like Zoloft or why doctors don’t go from a first-line drug like Zoloft or Prozac to Wellbutrin instead of say Effexor, which strikes me as a nuclear bomb. But I’m not doctor, so take this with a grain or three.

        • Protagoras says:

          I had a bad reaction to Wellbutrin, but not to Effexor, and I’ve heard a lot of anecdotes from people who also had bad Wellbutrin experiences. It is entirely possible that anxiety is involved, as you suggest, but it seems to be a drug that affects different people quite differently, and the unpredictability may be a reason it isn’t a first-line drug.

        • agmatine says:

          Wellbutrin is an excellent drug though quite it has quite promiscuous (and active) metabolites. I had excellent results with high dose Wellbutrin when combined with a mood stabilizer / anticonvulsant but I have a creative pdoc. Wellbutrin trials tested up to 1500mg but seizure risk lowered max to 450mg. I was on 600-900mg with a low dose of carbamazepine (I have bipolar 2) but lamotrigine would work well too probably.

          It’s an excellent drug and despite what it may seem, it IS one of the most frequently Rx meds, especially as augment to SSRI to treat anhedonia or sexual dysfunction.

    • avturchin says:

      You may look on drugs similar to ketamin. The most promising is memanatine. I used 3 mg every 3 days and had good results for depression. Remember, that you are interested not in immediate effect of the drug, but on it afterglow resulting from probably upregulation of NDMA receptors.

  4. Broseph says:

    With regards to their bannings effect on drug development it’s hard to overstate just how bad it probably is. If you look at the history of pharmaceuticals you see a series of serendipitous discoveries. Sometimes these molecules are good to go, like aspirin, other times they need some tweaking but give us the invaluable tool of letting us know what the end product will look like ( cocaine). But it goes even further then that often these molecules help define what system the pathology effects which ultimately leads to the discovery of other agents. Hell since the body often has broad mechanisms that show up again and again they often give us an idea as to what we should be looking for in other pathologies.

    • TrivialGravitas says:

      Aspirin is a tweaked molecule, based on salicin (primary active ingredient in white willow bark). It’s not serendipitous. Salicin rich plants have been known fever and pain reducers for at least as long as writing has existed. There’s no serendipity there, they took existing medicines, tweaked them, and came up with something cheaper and slightly better.

      • Broseph says:

        No the serendipity in the case of Aspirin is that they turned out to be great anti-platelet agents, more important than their original use probably. Normally when we discover a major side effect of a commonly used medication it’s that they cause heart attacks not prevent them.

        • Eric Rall says:

          I’ve been wondering when Aspirin’s anti-platelet properties became widely known ever since I heard (via TheGreatWar channel on Youtube) some new-to-me details about Rasputin’s rise to prominence. I’d known that Rasputin had gained influence with the Czarina after her son recovered from an extended period of hemophiliac bleeding soon after Rasputin took over the son’s care. The part I hadn’t known was that the Czarevitch’s doctors had been giving him aspirin, and it’s now believed that Rasputin’s apparent success was due to him taking over from the doctors and stopping the aspirin.

          So the question is, were the Czarevitch’s doctors guilty of malpractice because they should have known that giving aspirin to an actively-bleeding hemophiliac was a bad idea, or did they make an understandable mistake that’s only shocking with the benefit of hindsight informed by a century’s worth of advances in medical knowledge?

          • Vermillion says:

            Wow, that’s a really interesting idea about ol Raspy, do you have a link?

          • Eric Rall says:

            Here’s my original source (youtube)

            Here’s a corroborating reference (Google Books)

          • Broseph says:

            I believe the clinical trials establishing its efficacy as an anti-platelet were conducted in the 1960s.

            Though the effect is probably large enough that it’s not impossible that individual doctors could have noticed patients increased the propensity to bleeds.

  5. nelshoy says:

    Why do MDMA and Ketamine count as 21st century developments when they were both developed and used for different purposes much earlier?

    The pharmaceutical industry is searching for novel molecules, the “discovery” of ketamine vs. pimavanserin are not equivalent processes. If you’re talking about new studies finding known drugs helping with depression, you should probably add Botox and other things too.

  6. mzanonmental says:

    I’m a little suspicious trying to calculate the odds of a single chemical having two forms, one of which is a really exciting analgesic, and the other of which is a really exciting antidepressant, by two different mechanisms. It sounds too much like finding some new chemical compound whose solid form is a room-temperature superconductor, and whose liquid form catalyzes cold fusion, by two totally different mechanisms. It seems a little too lucky (see here for some ketamine skepticism, and here for my response).

    Ketamine is chiral, so such a dual-headed monster isn’t as unlikely as you might assume. What were the odds that one enantiomer of methorphan would be Robitussin (an SRI and NMDA receptor antagonist) while its sinister twin would be Levo-Dromoran (μ-opioid agonist analgesic)?

    edit: in fact, check out Muller, J., Pentyala, S., Dilger, J., & Pentyala, S. (2016). Ketamine enantiomers in the rapid and sustained antidepressant effects. Therapeutic Advances in Psychopharmacology, 6(3), 185–192.

    • Eric Rall says:

      Chirality is where my mind went, too. Specifically, D-methamphetamine is a strong stimulant that’s clinically useful in small oral doses for the usual things stimulants are prescribed for (ADHD, narcolepsy, overeating, etc) and in larger doses and other methods of administration is a highly addictive recreational drug. And meanwhile, L-methamphetamine’s main effect is vasoconstriction and is available over the counter as a nasal decongestant spray.

  7. Bram Cohen says:

    Psilocybin also may be miraculous against OCD, and LSD definitely helps with cluster headaches.

    The other problem with the pharma’s approach is that it not only avoids anything with side effects which are too strong, it avoids things with side effects which are too much fun. Normally you’d expect people liking a drug to indicate that it’s doing something good, with the important exception of addiction, but addiction isn’t the only thing drugs do.

    A lot of shulgin’s drugs really are onerous – they tend to last for days and be fairly unpleasant. The ones which have made it into widespread use are the best of the bunch.

    If you’re going down the list of psychedelics for what might also be useful the next ones up are probably (in no particular order) mescaline, DMT, and 2CB. Given the hit rate of other popular psychedelics, checking if those are useful in treating anything would probably a be a good idea. It also isn’t going to happen any time soon.

    • JohnWittle says:

      LSD is derived from the wheat mold ergot. The pharmaceutical industry has already used that connection to discover other ergot-based drugs with LSD’s psychoactive effects which work just as well on migraines and cluster headaches. Any prescription critical migraine medication is gonna look a little lysergic.

    • gwern says:

      There’s also LSD for alcoholism and addiction in general (see AA; I think there were at least a few tiny trials of that before LSD was banned?), as well as the current ayahuasca fad which aside from more generic benefits is often said to help addictions (not sure if that has any formal research yet). Nobody invented LSD or ayahuasca for treating addictions, people just noticed that.

      (Also hey, it’s John Wittle! Good to see you’re out of jail apparently. Also, you still owe me 1 bitcoin for my soul. 🙂

  8. Bugmaster says:

    I don’t know anything about pharma, so I apologize for asking such a n00b question, but still: how difficult is it for pharma companies to publish a medication which is either addictive, or has a high potential for abuse, or both ? For example, if someone develops a new morphine analog that is highly effective at suppressing pain, but only barely less addictive than actual morphine, then what’s the next move ?

    If it’s extremely difficult to get such a drug approved, this might be the reason why the pharma industry overlooked MDMA until recently: it’s just not worth the hassle. To be fair though, if you make this process too easy, you risk flooding the market with tons of super-powerful, super-addictive drugs, and presumably having a population that is strung out all the time is not a high-utility proposition…

    • Nornagest says:

      MDMA’s addictive, but it’s nowhere near as addictive as just about any opioid you’d care to name. And new opioids were still getting approved pretty recently.

    • LukeReeshus says:

      Well, it’s true that MDMA was “not worth the hassle” of mainstream production and therapeutic usage. Why was it such a hassle though?

      After receiving and considering all the evidence admitted during the hearings, Judge Young issued his findings and recommendation on May 22, 1986. In a comprehensive opinion, Judge Young found that MDMA did not meet a single one of the three criteria necessary for placement in Schedule I. Judge Young reported that MDMA had a safe and accepted medical use in the US under medical supervision. Furthermore, he found that the evidence failed to establish that MDMA had a high potential for abuse. Based on his thorough examination of the evidence, Judge Young recommended that MDMA be placed in Schedule III, which would allow doctors to use it in therapy and prescribe it, while still keeping it unavailable to the public at large.

      Administrator Lawn refused to accept Judge Young’s recommendation. In Administrator Lawn’s opinion, because MDMA was not an FDA approved drug it ipso facto lacked both any currently accepted medical use in treatment and an accepted safety for use under medical supervision. Administrator Lawn also averred that Judge Young gave too much weight to the testimony and evidence of doctors and patients, and not enough consideration to studies on rats, or the lack of FDA approval. In a flat rejection of Judge Young’s recommendation, Administrator Lawn decreed that effective November 13, 1986, MDMA would be permanently placed in Schedule I, not Schedule III.

      • Error says:

        My working assumption is that nobody making these calls actually cares about harm vs. benefit, they’re just opposed to any drug that can be used recreationally on principle; that is, they consider “getting high” a harm in and of itself.

        (Except nicotine and alcohol, because…well, because nothing particularly principled)

        • GregQ says:

          (Except nicotine and alcohol, because…well, because nothing particularly principled)

          Really? you missed the whole “Prohibition” experiment in the US?

          “Banning a widely used substance leads to great increases in crime, so don’t do it” is an entirely principled position, IMAO

          • Enkidum says:

            Well yes, that is the principled position, but exactly the same is true of weed, which is notably less harmful, and true of pretty much all other prohibited substances (although with the exception of psychedelics they tend to be pretty harmful).

          • Error says:

            Given that I was born fifty years too late, yes, I missed it.

            “Banning a widely used substance leads to great increases in crime, so don’t do it” is an entirely principled position, IMAO

            I agree; but as Enkidum notes, it’s not a principle that appears to matter to the people In Charge.

          • Controls Freak says:

            “Banning a widely used substance leads to great increases in crime, so don’t do it”

            Can we change that to, “Banning a substance that can be made by leaving food in a cabinet for too long and which can’t be banned entirely for a variety of cultural (religious) reasons might not lead to much of a measureable increase in major crimes, but changing political contexts and economic factors might cause you to reverse course.” Pithy additions like, “…so don’t do it,” or, “…so go on and do it,” are probably still up for grabs.

          • random832 says:

            @Controls Freak

            Banning a substance that can be made by leaving food in a cabinet for too long

            I thought about mentioning this, but it seemed too isolated-demand-for-rigor-ish for it to not be more or less equivalent to “weed is literally a weed”.

          • Deiseach says:

            But bans tend to happen because there’s a call for them. People are always looking for legal(ish) highs; somebody introduces “traditional native plant used by shamans for five thousand years” into a Western society that is not going to use it for spiritual enlightenment but to get a buzz; a small but not insignificant proportion of people try this; inevitably something happens (drugs gangs decide this is a lucrative additional revenue stream to offer alongside their existing range, or people try synthesising it, or there is selective breeding to make the plants deliver even more of a bang, and some kid takes too much at a party and dies).

            Then comes the call “Something must be done!” and the government of the day bans it.

            It might be better to leave it like alcohol and nicotine, but it’s a very tough-minded politician who, in response to a tearful mother’s TV appeal that “my beautiful 17 year old daughter with everything to live for died because some evil pusher at a party persuaded her to try cake“, will reply “Well, life is tough. We’re not going to ban Cake, and 17 year olds will just have to look out for themselves”.

          • The Nybbler says:

            @Deiseach

            The fact that the drug gets you high is reason enough for the ban, for the drug warriors. The side effects are mostly an excuse.

          • GregQ says:

            @Enkidum @Error

            You’ve given an argument for banning things before they become as widespread as smoking and drinking.

            Which is exactly what the drug warriors have tried to do. No?

          • Controls Freak says:

            weed is literally a weed

            This is partially a point in favor of similarity between alcohol/marijuana and partially still a point of difference. My argument is not, “Alcohol is different in every way,” and it’s definitely not an isolated demand for rigor. It’s simply saying that we have to be honest about when things are similar and when they’re different. Oh, and we have to be honest about history, too.

          • Enkidum says:

            “You’ve given an argument for banning things before they become as widespread as smoking and drinking.”

            Uh… no, only if you assume there is some good that comes of banning these things. The vast majority of people who use heroin (never mind weed) suffer no particular negative consequences. Destabilizing entire continents and ruining the lives of millions because you have a shitty puritanical attitude towards other peoples’ pleasure is not a good look.

          • Error says:

            @GregQ

            I acknowledged that your suggestion was principled and stated that it is not a principle drug warriors appear to care about. I gave no opinion on whether I agreed with it myself.

            And even if I did, “don’t ban things that are widely used,” != “Do ban things that might become widely used.”

        • rahien.din says:

          IIRC, the process whereby a drug gets scheduled includes the following delightful protocol. Not even joking :

          1. A bunch of former drug abusers are assembled in a testing facility
          2. Each one is given gradually increasing doses of the drug in question
          3. After each escalation, a researcher asks them, “How do you feel? Did that make you feel good?”

          Depending on the dose at which it made them feel good, the drug is scheduled.

          • LukeReeshus says:

            Drug prohibition is not a public health initiative. It is a crusade against the distraction of personal pleasure, which Christians include in the category of “sin.”

            Although there is a Progressive element to it as well (lest anyone think it is purely a “right-wing” phenomenon).

    • random.name.0815 says:

      For example, if someone develops a new morphine analog that is highly effective at suppressing pain, but only barely less addictive than actual morphine, then what’s the next move ?

      You are speaking about methadone. Or buprenorphine. But opioids. Both addictive, by some accounts methadone is much harder to wean off than heroin. So, if you have something that is effective but addictive the next step is: formulate a problem that is solved by this substance, push to market, profit.

      If it’s extremely difficult to get such a drug approved, this might be the reason why the pharma industry overlooked MDMA until recently: it’s just not worth the hassle. To be fair though, if you make this process too easy, you risk flooding the market with tons of super-powerful, super-addictive drugs, and presumably having a population that is strung out all the time is not a high-utility proposition…
      MDMA has negligible addictive properties. I’d place it far below alcohol. It feels good, so of course there is a desire to repeat. Unfortunately, you will get diminished returns on repeat usage very quickly (days, not weeks) so it is very unlikely for people to develop an “addiction”. The kick just does not come in anymore. This is the same with any drug, but it happens very quickly for MDMA. You won’t be able to take it often and long enough to get to the point where you “need” it to function, like it would be the case with alcohol addiction after extensive, longterm consumption.

  9. Nornagest says:

    trying the top hundred craziest things Alexander Shulgin dreamed up on whatever your rat model is

    I’ve said in these comments before that every so often I wake up wanting to be a mad social scientist. You’re not exactly convincing me otherwise with phrasing like this.

  10. shmorcus says:

    The problem here is that you focus on the substances that treat psychiatric disease while pharma industry focus on the receptors in brain.

    Simplifying, there are something like 10 major brain neuromediators modulating mood and about 10 receptor subtypes and service proteins for each of that mediators. All of your examples hit one of those targets.
    There is no sense for the science to test all of zillion possible chemical substances, if they can focus on the identifying mechanisms involved in the mental illness.

    The way to identify that mechanisms is pretty creative. It depends much on how deep is the scientists understanding of the biological function of each mediator and its maintenance. Major problem is that human experiments are very restricted but animal models of mood disorders are elaborated not that good.

    Of course, the fact that some substances are banned makes problem a bit more complicated. But that is not the problem of substances – there are a lot of analogs for every receptor type acceptable for use on animals or on cell culture in laboratory. But the real problem is in understanding biological role of brain chemicals by the multiple researches, where substance testing has pretty limited potential.

    For example, in case of MDMA, we first got the model of the stress and the role of serotonin transporter in its effects on mice and then tested MDMA (as serotonin transporter modifying substance) when it got legally to test.

    In fact, a lot of people think that one form of ketamine is hallucinogenic (and extremely effective against chronic pain) and another form (or its metabolite) is the antidepressant.

    Its just a bit different. Ketamine is active on one of the glutamate receptors subtypes (NMDA) and its metabolite is active on the other – AMPA.
    Role of AMPAkines on mood, brain development and building new synapses seems to be very promising now.

  11. harland0 says:

    Timothy Leary has a lot to answer for.

    He did his royal best to frighten the crap out of people. “I’m going to give your children LSD and afterwards I’m going to take them away, and they’ll never want to talk to you again! Muhahahaha!” People believed him. He did a tremendous amount of damage at exactly the right time, when these drugs were new and impressions easily formed. The creation of a drug culture by the far left and the hippies didn’t help, either. One could scarcely have fictionalized a worse scenario for introducing the world to hallucinogens. People back then thought it was a hoot to give people hallucinogens and then tell them about it after dosing them. Combine this with the CIA’s experiments and their proclivity for unethical behavior (which continues today) and you have today’s attitudes which clearly harm more than help. It’s a big shit sandwich and without Timothy Leary’s death’s head scaring the lights out of people, it would not nearly have been as bad.

    • LukeReeshus says:

      Seconded.

      I find the early psychedelic era fascinating and have read a lot about it (Albert Hoffman’s LSD: My Problem Child and Jay Steven’s Storming Heaven: LSD and the American Dream are both excellent reads), and I’m pretty sure I have a lower opinion of Timothy Leary than the average drug warrior.

      At the same time, I’m pretty sure the cultural backlash against psychedelics was inevitable, because them getting out of the lab was inevitable. Timothy Leary just happened to be the one in the spotlight.

    • Actually, Ken Kesey was the real screwball. Timothy Leary actually criticized Kesey for being too cavalier about the use of psychedelics. Leary wanted the drugs to be approached carefully, ritualistically, and constructively–for self-exploration and self-experimentation. Kesey wanted to blow people’s minds. Leary was actually the relatively “responsible” one in the psychedelic community at the time.

  12. LukeReeshus says:

    This post seems to be driving at the gap that exists between “true psychological health” and what are society deems to be “normal psychological functioning.”

    I tend to think that gap is wider than most people do. Which is probably why I think about the War on (people who use) Drugs differently than most people do.

    Anyway, three cheers for party drugs!

  13. SorenMind says:

    Another thing to note is that there are probably only so many ways to “smack the brain really hard” and most of them were discovered by mid-20th century, leaving little to find for the pharma researchers. Mostly, what you can do is play with dopamine, serotonin, NMDA/glutamate, choline, endorphins, GABA, various hormones, and some less obvious things like cannabinoid and GHB receptors. When we find something new now, and even in the times of Shulgin, it’s usually very similar to existing drugs.

    In fact I’m having trouble thinking of a single counter example, anybody got one?

    • Fractalotl says:

      Salvinorin A can “smack the brain really hard” via a mechanism that I think is different than what you mentioned — like endorphins, it’s a kappa opioid agonist, but it’s also a potent psychedelic. It’s quite different than the way most other psychedelic compounds work, as far as we know!

      Although — the Salvia divinorum plant certainly has a long history of traditional shamanic use in the Mazatec region of Mexico, so perhaps this shouldn’t count as a recent discovery. Salvinorin A was first extracted from Salvia divinorum and described in 1982. I’m not sure about the rest of the research and recreational use timeline, but Australia was the first country to ban Salvia in 2002.

      Peter Addy at Yale has done some really fascinating research around salvinorin A, and presented at the recent Psychedelic Science 2017 conference:

      http://psychedelicscience.org/conference/plant-medicine/clinical-potential-of-the-plant-salvia-divinorum

  14. chrism says:

    A drug that makes you feel extreme side effects for a few hours – but also has very strong and lasting treatment effects – is better than a drug with few side effects and weaker treatment effects.

    A perfect example would be chemotherapy for cancer. Monthly infusions of fludarabine, cyclophosphamide and rituximab didn’t make me feel too great, but so far I’ve had two years of life that I wouldn’t have had without those side-effects. When the stakes are high, side-effects become much more tolerable, and the stakes can be just as high for someone with a severe treatment-resistant depression. Thus far, leukemia has been a piece of cake compared to the depressive episode I had 15 years ago.
    For all the profits that can be made with a me-too-oxetine, it seems the stigma of mental illness extends to keeping research into novel psychiatric drugs back in the scullery with Cinderella. It is also worth noting that we are willing to tolerate, on our patients’ behalf, some pretty nasty side-effect profiles from not terribly effective drugs when they are used on the underclasses of less fashionable and more destructive mental illnesses. Just look at how much ‘novel’ antipsychotics shorten lifespans through the induction of metabolic syndrome. Terrible drugs, but we have failed to come up with anything better – and I suspect that’s because of a lack of interest in the most stigmatised mentally ill – the mad – and not because it is pharmacologically impossible to do better.

  15. enkiv2 says:

    The narrative that recreational drug users are ‘self-medicating’ is probably at least somewhat true — i.e., some large portion of the population of recreational drug users (I’d guess over ten percent, and I’d also expect them to be the most dedicated and consistent of the lot) are using these drugs at least partially for the kind of side effect that would be a primary effect in a clinical setting, rather than purely for getting high.

    So, how is it particularly surprising that a very large population of people who are extremely driven to treat their own illnesses and have access to a wide array of substances would sometimes find several that work really well — or that, on the other hand, large organizations who are mostly interested in patenting variations on known chemicals before their competitors would not have the same kind of success as big populations of rapid, driven experimenters?

    We also have to consider that Shulgin isn’t quite the outlier he looks like. Street drugs that are synthetic have to be synthesized by somebody, and if they aren’t currently in use in medicine then that somebody has to be a chemist who is specifically working on making street drugs. Lots of smart people take a lot of drugs (novelty-seeking behavior), and people with a pharma chem background aren’t immune to being interested in getting high (though they might have a better idea about the risks involved with certain kinds of chemicals). Presumably some of the same people who do research for big pharma during the day go home and synthesize acid and MDMA. In other words, it makes sense to consider the entire street drug culture as a whole as a kind of right-libertarian pharmaceutical industry R&D lab. Just as we can predict TV show home video sales based on the rate at which recently-aired episodes are pirated, we can predict interesting drugs from what’s popular in the discos.

    • shrikesnest says:

      This is what I was hoping to see in the comments. The line between recreational drug user and self-medicating drug user is, in my experience, very blurry. Everyone I know with anxiety problems spent a frustrating year or two trying to make benzos work, and then flushed (or sold) them and started smoking weed instead. A large number of them increased their weed usage thereafter, until their pattern of behavior is indistinguishable from any other marijuana enthusiast, but some part of their drug use is still linked to treating their anxiety.

      I wonder how many people taking MDMA at the club are dealing with untreated cases of PTSD. I think it’s about impossible figure this out definitively, and speculating would be pointless, but personally I believe that there are a lot of undiagnosed cases of PTSD, especially in the USA. People are so used to the dramatic treatment of traumatic events in movies and television that they barely recognize the real thing when it happens to them, and they never connect their constant nightmares and panic attacks to what they went through – they’d just rather not think about it.

  16. In engineering the ability to have rapid iteration is incredibly powerful. Trying something, failing, and then trying something else based on the failure not only makes progress in the obvious way, it builds your intuition about the problem. The reason the Wright brothers were the ones to fly first was that unlike other teams they could turn their machine around in a matter of days after a test.

    So it isn’t surprising to me that street drugs could advance technically much faster than pharmaceutical companies can. At the same time pharmaceutical companies are building up abstract knowledge in a way that might be very useful once it’s complete enough.

  17. aciddc says:

    The large effect size motivation seems reasonable, but I think an additional meta-level factor is that these companies aren’t really trying that hard to ‘cure’ anything. They have a lucrative business in selling drugs to the mentally ill, and are perfectly happy with that. A pill that needs to be taken more rarely could even be harmful, since they’d sell fewer of them. And even worse, if people are cured they might not buy any pills at all! I don’t know if pharma execs are really sufficiently cacklingly evil to think of it explicitly in those terms, but that incentive structure is certainly not going to do progress any favors.

    • Deiseach says:

      And even worse, if people are cured they might not buy any pills at all!

      But can ketamine cure depression? We know it makes you feel good, but that is not the same thing. And we’ve been down this road before – I don’t know how many of you remember when Prozac was first introduced, but people were raving about how it completely changed their lives, then people who were not the diagnosed for the drug wanted it and some were advocating “put it in the water supply” half-jokingly.

      Who now thinks Prozac is the wonder drug that will cure permanently the depressed and make the ordinary person even better, happier and living their best life now (as opposed to one more tool in the box)? Pharmaceutical ketamine for depression might go the same way, the way CBT is being pushed (at least over here, we always lag behind the USA) as the One Weird Trick that will definitely fix you right up no matter what the problem is, from feeling suicidal to eating disorders!

      • Nornagest says:

        But can ketamine cure depression? We know it makes you feel good, but that is not the same thing.

        Ketamine is a powerful dissociative. It has lots of interesting effects, but isn’t reliably euphoric — the people that take it are usually looking for novel mental states more than anything else.

        And that’s really what makes it interesting here. We know a lot about how messing with the serotonin system (e.g. Prozac, an SSRI) interacts with clinical depression — that is, it kinda works for some people, but the effects are subtle and require ongoing intervention. Ketamine affects a completely different set of systems (it’s an NMDA antagonist, but there’s some weird stuff going on), so the fact that it affects depression at all gives some insight into what’s going on under the hood.

        • Deiseach says:

          But does it have a long-term effect, or is it a case of “yeah gonna need a top-up every fortnight”? Because if we’re oohing and ahhing over ketamine as a wonder drug for the depression nothing else can shift, I think we need to be very damn clear about what is the “hits the depression” part of it and what is the “gets you off your face so that when you’re orbiting Pluto, you don’t care that you’re still depressed” part.

          And how long this lasts, and how much maintenance dosing you have to do. I mean, we’ve gone down this path with Prozac (and every other new wonder drug that is going, this time for sure, to cure A, B or C).

          • Nornagest says:

            That’s another interesting thing. The metabolic half-life of ketamine is something like ten minutes. It’s cleared from your system very very quickly. So if we’re talking about effects on depression that last for weeks or months, then there’s really only two options: either it’s a long-lived (and non-psychoactive, or you’d still be stoned months later) metabolite of ketamine that’s actually doing the work (Wikipedia suggests (2R,6R)-hydroxynorketamine as a candidate), or it’s doing something persistent on, for lack of a better word, the software level.

            The latter sounds enough like hippie stuff that I’m kinda leaning towards the former. But on the other hand it’s pretty suspicious that basically all the powerful psychedelics — including a number of structurally unrelated molecules with completely different mechanisms of action and metabolic routes — show promise in treating hard-to-treat mental illnesses.

          • herbert herberson says:

            “Have you tried turning it off and back on again?”

          • TheEternallyPerplexed says:

            @herbert
            That is Electroconvulsive therapy.

          • vV_Vv says:

            That is Electroconvulsive therapy.

            But it kinda makes sense, doesn’t it?

            Let’s hypothesize that what we call “depression” is the sum of negative thoughts and emotions accumulated over time, which may at some point cause a self-sustaining feedback loop.

            If you “press the reset button”, using ketamine or ECT, the negative thoughts will go away, and at least for some time you will not be depressed. If the depression had no persisting cause other than the feedback loop, then the cure will be definitive, if it had another persisting cause, whether biological or environmental, then the negative thoughts will start to accumulate again, until the next reset.

          • jes5199 says:

            I have actually tried Ketamine. It’s not fun. I spent a couple hours stuck on the couch, feeling like I was watching myself from the outside, like “look at that guy, just stuck on the couch.” And then gradually returned to normal. And then the next day my mind was clear and I could, like, get up and go to the grocery store without the vague emotional fog disrupting everything like it had been for months

          • Janet says:

            Well… nobody quite knows, as this hasn’t been studied properly. But to try and answer your question: as noted by several other commenters, in the US, ketamine is a schedule III drug (meaning, roughly, that there is a moderate potential for abuse, but also good therapeutic uses as well). It is approved for use as an anesthetic, both for humans and animals.

            Under US law, physicians generally can prescribe drugs “off-label”, that is, without FDA-approved efficacy trials, if they make a professional judgment that the treatment is warranted. So, there are numerous (50-60) clinics which are using ketamine for severe depression in the US, generally only after all other treatments have been tried and failed. Based on that anecdotal evidence, ketamine is NOT a one-and-done treatment, but rather is an initial run-in period, followed by periodic “booster shots”. At these doses, most patients don’t hallucinate or get high; rather, they typically report feeling “dissociated” (observing themselves from the outside, detached from emotions, hard/impossible to initiate movement, etc.) for perhaps as much as an hour.

            For the (large minority) which report positive results, they describe it as making the depression simply vanish. In particular, the ability to initiate actions freely (get up, go to work, make decisions, etc.) seems to return. The single biggest problem reported is that, for some patients, the depression can return full-force, almost instantaneously. This is a very severe risk for impulsive suicides or self-harming, since there is no warning and no chance to prepare or get help, no coping methods in place, etc. Nobody knows why it works, or why it stops working; but it doesn’t appear to be primarily because the drug (or a metabolite) is actively binding with a receptor, as the time scaling is all wrong. Perhaps it’s more like ECT, and pushes the brain into a different locally stable equilibrium?

            Several commenters have expressed interest in “self medicating” with ketamine, either buying on the street or doing some “pharma tourism”. I would urge you to NOT do that, because you really, really, really need a physician to help you do this safely. And you can do it legally and safely, at one of these clinics. If you are going to respond, you’ll know that after the first couple of doses, and that can guide your further decisions. But please DON’T try this on your own.

  18. ratireli says:

    Scott, I can confidently predict, based on the substance fo this article, that you will never be hired to head the R&D department of any large pharmaceutical company. So be sure to direct your future career fulfillment ambitions accordingly.

  19. baconbacon says:

    For decades, pharmaceutical companies have been coming out with relatively lackluster mental health offerings – aripiprazole, pimavanserin, and all the rest. And when asked why, they answer that mental health is hard, the brain is the most complicated organ in the known universe, we shouldn’t expect there to be great cures with few side effects for psychiatric diseases, and if there were we certainly shouldn’t expect them to be easy to find.

    And this would make sense except in the context of ketamine and MDMA. Here are some random chemicals that affect the brain in some random way, which people were using mostly because they felt good at raves, and huh, they seem to treat psychiatric diseases much better than anything produced by some of the smartest people in the world working for decades on ways to treat psychiatric diseases. Why should that be?

    I think you are missing the actual (likely) casual relationship. Imagine an anti depressant that was very effective in treating those afflicted, with limited side effects that didn’t do squat for someone without depression. That is a heck of a parley, realistically something that can turn depression around without significant side effects is going to make people who aren’t depressed feel pretty good in some way. The current set up of heavily restricting anything that might be abused by people who like to feel good on a Saturday night automatically cuts out (or restricts) investigation into the exact compounds that will be the most helpful. It isn’t a matter of volume, its a matter of path dependency.

    For me it’s about the weird inability of intentional psychopharmaceutical research to discover anything as good as things random druggies use to get high.

    You have the history of humanity backwards. Feeling good is a huge motivator, and isn’t reserved for a tiny subset of the population. “Random Druggies” presents an incorrect image of what people do and what they like. Alcohol, nicotine, caffeine and marijuana are all widely used, and not just in a single ‘everyone likes this” form. Alcohol is made from grapes, barley, cactus, potatoes, corn, fruits, sugarcane, rice, wheat, etc, etc. Hops have basically no nutritional value outside of brewing, and they have been bred for centuries with this single purpose in mind.

    The pharmaceutical industry shouldn’t be juxtaposed with random druggies, they are both part of a larger set which includes virtually the entire world population, and this is why the FDA is so god damn harmful.

  20. Deiseach says:

    Since I had no luck convincing my doctor to prescribe me ordinary anti-depressants, I don’t fancy my chances heading in and asking “Givvus a dose of them horse tranquilisers, willya?” 🙂 So I can’t see ketamine in my near future. (Never mind that the whole intravenous part makes me queasy).

    I wonder does it work on the same lines as alcohol? You’re still depressed, but now you don’t give a damn. Or you’re still depressed, but you’re high as a kite so you don’t care, until you come down and have to go in for your weekly top-up. I think there’s a reason that conventional anti-depressants only have a small, gradual, cumulative effect, and part of it is that it’s very hard to decide taking “if a little is good, more would be even better!” where “a little” means you feel slightly less awful and “more” would only mean you feel somewhat more less awful, unlike “whoa this is great! hey, if one tablet a day does this, how would I feel if I took six?”

    How do you tease out the “woo, I feel great!” effect of these drugs from the “yeah, they actually do affect the depressed part of the brain”? Not to mention that any medical versions of these are going to need to water down considerably, if they can’t get rid entirely, of the “woo, I feel great, cosmic love and peace!” effects? Because the potential for abuse is right there staring us in the face; if you can get Special K on prescription meant for treating depression, suddenly a lot of people will be coming down with depression. Never mind the opiod abuse problem already existing, ketamine is literally a horse tranquiliser and some person thought “Hey, it’s a great idea to take this and see what happens!” for harmless recreational fun (yes I know it started off trialled in humans and is still used as an anaesthetic, but see the comment above about junkies robbing veterinary offices to get the goodies).

    I dunno. I find it very hard to believe “people take stuff to get off their faces and it turns out to have legitimate medical application” is that easy. It may be my natural wet-blanketness, but I think sometimes you can only hope for “you’ll feel less terrible” and anything which makes you go “yeah top of the world, ma!” has strings attached. Cocaine started off (in European usage) as an anaesthetic for use in eye surgery (Arthur Conan Doyle encountered it in this context when he was specialising in ophthalmology) and Freud was one of the early advocates of “this harmless new non-addictive wonder drug which will help us treat patients addicted to morphine!” (To be fair to Freud, he soon realised that um, it wasn’t that miraculous).

    Yeah. Look how that turned out.

    • baconbacon says:

      I wonder does it work on the same lines as alcohol? You’re still depressed, but now you don’t give a damn. Or you’re still depressed, but you’re high as a kite so you don’t care, until you come down and have to go in for your weekly top-up

      The high lasting a week+ would be pretty extreme. People I know who use weed to handle their depression in this way are smoking 3-8 times a day, alcohol abuse tends to be daily, even if it was the same effect (which seems unlikely to me) it would be a huge improvement over those other avenues.

    • sandoratthezoo says:

      My (very limited) observations of recreational use of ketamine would suggest that the “high as a kite” period lasts about an hour, not a week.

      • Deiseach says:

        I was wondering more about the half-life of it, once the “high as a kite” part wears off. If it’s really knocking your depression for six, it must be doing something in some measurable way, so what is floating around in the bloodstream/past the blood-brain barrier/feck it, it’s in your fat stores and being released gradually, I dunno how this works?

        EDIT: And thank you, Scientific American:

        Gould and his colleagues used a battery of behavioural tests in mice to show that one of ketamine’s breakdown products—a compound called (2R,6R)-hydroxynorketamine—is responsible for much of the drug’s antidepressant effects.

        And to Gould’s surprise, the metabolite did not cause side effects in the mice even at doses nearly 40 times higher than the antidepressant dose of ketamine. The mice also did not tend to press a lever to receive the metabolite when given the option to self-administer it.

        I’m a little suspicious trying to calculate the odds of a single chemical having two forms, one of which is a really exciting analgesic, and the other of which is a really exciting antidepressant, by two different mechanisms.

        Note the chirality in the name and I see by Wikipedia that there are four possible stereoisomers, so yup, we could be looking at “the dextro rather than the laevo-rotation version is what’s doing it”.

        Looks like several someones have been doing the heavy lifting on this:

        After recording baseline activity for 1 h, mice received drug (dashed line) and locomotor activity was monitored for 1 h. Administration of (2S,6S) HNK dose-dependently changed locomotor activity (a), whereas administration of (2R,6R)-HNK did not (b).

        Damn it, I can’t find out how long the metabolite binds to the receptors (which is something that I want to know, if the effect lasts one to two weeks) because they keep killing their rats after four hours to dissect the brains. Great, that tells you how fast ketamine breaks down, but it doesn’t tell me what initial dose of the metabolite a human should take for the observed benefit, or would taking small doses every day be better, or what?

        Somebody help an ignorant woman out here and tell me what’s what!

    • Garrett says:

      Please stop referring to ketamine as a horse tranquiliser. I mean, it is. But it has also maintained a long use as pediatric anesthesia. I volunteer in EMS and have been trying to get ketamine for use as a non-respiratory-depressing anasthetic on ambulances. But the politics and optics of “you want to carry horse tranquilizers” make this a greater challenge. It’s made even worse in that we’re facing overdose deaths from carfentanil use, which actually is only approved for veterinary use.

      • Deiseach says:

        Well, if you want people to stop calling it horse tranquilisers, (a) make it so that the way most people hear of it isn’t either in animal use – for us rural types – or on the news as ‘six people got high on party drug’ (b) I sympathise about the “it has legitimate use as an anaesthetic” but you have to face the fact that, if people are breaking into vets’ offices in order to get their hands on it, then ambulances regularly carrying it aren’t going to be much safer and yes, you have to address the optics and the politics because the first time some idiot tries to knock over an ambulance outside a hospital and chaos ensues, guess what the public reaction will be? And it won’t be “hmm, a promising drug for the treatment of depression has an unfortunately popular reputation amongst certain persons who like to recreationally alter their brain chemistry, let us be measured in our response to this”.

        • Siah Sargus says:

          No, we’re asking you to stop calling it horse tranquilizers, because that’s a disengenous and non-central example of what Ketamine does, and precise language is a good habit to cultivate. The news will continue to be pandering, inflammatory, and sensationalized, and just because they are a ubiquitous voice, doesn’t mean that you have to imitate their flaws. You are a voice here as well. This is a thread about psychiatry, not veterinary medicine, and we are talking about Ketamine in that context.

          • Deiseach says:

            This is a thread about psychiatry, not veterinary medicine, and we are talking about Ketamine in that context.

            And I am pointing out that we are not discussing a new paper about an interesting molecule recently synthesised by the University of Woonsocket’s research lab, we are talking about drugs that already have a reputation and background from the 90s onward as party treats; that the general public has heard about in the context of raves and the War on Drugs, and that outside of that context, ketamine is known to people from a rural or farming background for its use in animal medicine.

            You are going to have to take all that into account when putting your case for “this is why we think it should be taken off Schedule I”, and you can be as sniffy as you like about the debased tone of “pandering, inflammatory, and sensationalised” debate but that’s the reality of the situation. No Minister or Secretary for Health is going to sign off on “sure, throw it around like snuff at a wake, boys!” without taking into account “and what will public reaction to this be and will it lose me votes in the next election and will the partisan media seize on this to paint me as the junkies’ enabler the next time some teenager does too much of the wrong pill at a house party and dies?”

            Eyewitnesses reported, at the time, party-goers were in extreme distress when they were found, with reports that some had slashed themselves with broken glass and that others were hallucinating widely.

            While five of the party-goers aged between 18 and 37 recovered quickly after hospital treatment, Mr Ryan never regained consciousness and died in CUH several days later.

            Dr Margot Bolster, the Assistant State pathologist, told Mr Comyn yesterday a postmortem examination had revealed Mr Ryan died from hypoxic ischemic encephalopathy — lack of oxygen to the brain — due to cardiac arrest from ingestion of 4-iodo-2 5-dimethoxy-n-(2-methoxybenzyl)phenethylamine — or 251NBOMe — a psychedelic drug known on the streets as N-Bomb.

            Mr Comyn noted the evidence and told Mr Ryan’s mother, Irena, and his sister, Nicole, that he was adjourning the inquest, pending the outcome of the criminal proceedings, for mention again in December.

            N-Bomb is part of a family of drugs which are synthesised in backstreet chemists in Eastern Europe and the Far East, and which are prohibited under the Misuse of Drugs Act 2015.

            Widely available online, and sold in tablet, powder, or liquid form, the drug produces intense hallucinogenic and psychedelic effects described as a cross between ecstasy and LSD.

            Hmm, should we cross this one off the list as a potential psychiatric medication? What’s the opinion here? I’m not snarking for the sake of it, this is precisely the publicity and formed opinion that you are going to have to overcome when discussing the use of psychedelics in psychiatry, so you’d better be prepared to roll up your sleeves and engage with the “but that’s horse tranquilisers, isn’t it?” response, and do it with more than a pained look of “don’t be so sensationalist” when you’re making your case.

          • rahien.din says:

            Deiseach,

            If I referred to phenobarbital as a mass suicide drug or a medication for elephants, I would not be incorrect.

            Sure : I would be making incredibly misleading statements.

            Sure : if in a discussion of neonatal seizures, I insisted on calling it “euthanasia,” I would be distorting the discussion by disregarding context.

            Sure : if someone told me “Stop calling phenobarbital an elephant suicide drug, that’s bad language and that sort of fecklessness decreases our ability to use the drug appropriately,” and I replied “If you don’t want me to promulgate misconceptions, don’t just tell me to stop promulgating misconceptions – instead, try to keep people from promulgating misconceptions,” I would be incredibly obtuse.

            But I wouldn’t be factually incorrect. Neither are you.

          • Deiseach says:

            Want to play this game? We can play this game!

            How horribly obtuse and incredibly misleading of many’s the Golden Age crime writer to use cyanide as a tool for murder, instead of the useful industrial agent in electroplating that it is! Why, this has given the general public the terribly distorted impression that cyanide is a dangerous poison!

            What a crying shame that arsenic, so important industrially, is associated in the minds of that same public with murder and painful death, thanks to irresponsible articles like this by those who disregard context!

            Dear dear, these unfortunate and irrational prejudices do hold back chemical research so!

            Look, if you can’t understand what is the problem I am trying to identify, then we’re talking past each other. Public perception has a hell of a lot to do with it, and if the public perception is “dangerous drug”, all your high-minded finger-wagging won’t do an iota to shift that perception and let psychedelics become something pharma companies don’t feel would irreparably taint their reputation to be associated with.

            Give me a suggestion as to how you would convince Concerned General Public that carrying ketamine in ambulances is a good idea, which does not rely on sneering at them as “incredibly obtuse”, and I’ll listen.

          • Nornagest says:

            It seems to me that if the concerned general public gets a veto over what goes into an ambulance, something went wrong long before we got to the scheduling stage. I don’t want the concerned general public making those decisions. I want someone that knows what he’s doing making those decisions. If that scares the public, the public will just have to live with being scared.

          • rahien.din says:

            People have well-adjusted perceptions of arsenic and cyanide. These are widely considered to be important for industry but very toxic. No one seems to be saying “I needed a new car battery, but I don’t fancy my chances heading in to the mechanic and asking ‘Givvus a slug of them poisons from antiquity, willya?'”

            And as such they fall into a vast category of known-to-be-dangerous-but-also-useful. No one seems to be saying “I needed a new smoke detector, but I don’t fancy my chances heading in to the store and asking ‘Givvus that thing that a teenager made fissionable isotopes out of, willya?'”

            There are no misconceptions here, so arsenic and cyanide (and americium) aren’t relevant.

            In contrast, if people hesitate to ask about legitimate treatments because they incorrectly think of those treatments only as “party drugs” or “horse tranquilisers,” that’s a case of a misconception having a very real impact on those people.

            But you seem to claim :
            1. The perception of ketamine as only a party or veterinary drug is wrong
            2. This misperception is causing harm, both personally to you, and societally as it inappropriately restricts access to legitimate treatments.
            3. How dare anyone wag their finger at you for knowingly promulgating this misconception.

            Weird.

            Edit:clarity

          • HeelBearCub says:

            @Deiseach:
            Holy kettle of fish you would be on the opposite side if this argument, wanting precision in language, if it was about something you know more about than the general public.

            And not only that, you would be in the exact same state of high dudgeon, claiming how awful people are for being wrong or misleading about something.

          • rahien.din says:

            HeelBearCub, Deiseach,

            All things considered, I should probably mitigate my personal height of dudgeon. Cheers to a good day, and Deiseach, good luck with your search for treatment.

        • rahien.din says:

          Garret : Please stop referring to ketamine as a horse tranquiliser. I mean, it is. But it has also maintained a long use as pediatric anesthesia.
          Deiseach : Well, if you want people to stop calling it horse tranquilisers, start telling people it isn’t a horse tranquilizer.

          This interchange kind of happened backwards…..

          FWIW, I am a pediatric neurologist and I honestly didn’t know that it is a horse tranquilizer. I use it for status epilepticus and my colleagues use it for procedural sedation. Great drug.

          if people are breaking into vets’ offices in order to get their hands on it, then ambulances regularly carrying it aren’t going to be much safer

          Ambulances also carry benzodiazepines (high abuse potential) and opioids (high abuse potential), and any of their controlled substances are well-secured. I doubt that the knowledge of ketamine’s presence increases their value as a target to any real extent.

          • Garrett says:

            I use it for status epilepticus

            Interesting. We usually use Valium for that (ketamine not currently being available). Is there a reason you prefer ketamine over Valium in status epilepticus? Are there any quality studies or position papers to support that?

            Ambulances also carry benzodiazepines (high abuse potential) and opioids (high abuse potential), and any of their controlled substances are well-secured.

            Yeah. Most controlled-substance thefts either involve armed-robbery (rare), or “internal diversion”, which is sadly common in people in emergency medicine and anesthesiology, apparently.

          • rahien.din says:

            Garrett,

            (Wasn’t expecting this question! So that may have been a rather too-prosaic summation, earlier. Here’s your wall ‘o text.)

            Should be more clear and say, ketamine is one of my nicer options in super-refractory status epilepticus. These are patients who have persistent or frequent seizures despite intensive (ICU) therapy. Those folks have already gotten lorazepam or diazepam, big doses of conventional antiseizure medications (levetiracetam and/or fosphenytoin and/or lacosamide for instance), and are on anesthetics (high-dose phenobarbital, and/or drips of midazolam, pentobarbital, or propofol).

            Ketamine is a nice option in those cases because of its unique mechanism of action of NMDA antagonism. For one, this is another way to attack the seizures, rather than slamming more drug onto the sodium channels and GABA system. For two, glutamatergic excitotoxicity is probably important in the morbidity and mortality of status epilepticus, so countering that activity seems like a good idea. For three, the common adverse reactions (agitation, anxiety, hallucinations) aren’t going to matter to unconscious patients, and the more-worrisome less-common ones (cardiovascular) are definitely not as bad as those caused by anesthetics, and at the very least will be monitored and mitigated in these ICU patients – I vastly prefer that to the metabolic acidoses associated with prolonged propofol infusions.

            The use of ketamine in these situations is gaining traction but there is a lot left to learn. Granted, this remains entirely in the domain of the ICU, and it requires establishing a continuous infusion.. Ketamine currently has no established or proposed role in the pre-ICU setting, and given its potential for abuse (either in patients accustomed to it, or via internal diversion) I doubt you’d have a leg to stand on if you wanted to push ketamine on the truck for status, and someone questioned your rationale / risk:benefit. YMMV.

            A selection from the literature :

            Retrospective review produced by some of the leaders in my field : Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013 Aug;54(8):1498-503.

            Interesting observation that hints at a distinct neurophysiology : Drug-induced EEG pattern predicts effectiveness of ketamine in treating refractory status epilepticus. Epilepsia. 2015 Apr;56(4)

            Narrative review of the topic : Ketamine for the treatment of refractory status epilepticus. Seizure. 2015 Aug;30:14-20.

            Protocol that will compare midazolam and ketamine as the initial stage III infusion in refractory status epilepticus : Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01). BMJ Open. 2016 Jun 15;6(6):e011565.
            Note that this is somewhat daring. Refractory status epilepticus is dangerous and can disable or kill in some proportion to the duration of the episode, and the duration of an episode of status predicts duration of future episodes. These folks are convinced enough of ketamine that they are deviating from established protocols in a randomized fashion, with the clinician having discretion to continue ketamine for up to a week. Badasses. Almost as cool as the ESETT trial.

            Aside : it’s interesting we are discussing this intersection between human and animal medicine, because bromides are an option in super-refractory status epilepticus. But you can’t get them from any human pharmacy (anymore). You have to buy them from a vet.

      • The Obsolete Man says:

        When I had general anesthesia for surgery recently, I found out that Fentanyl was used. I asked the anesthesiologist about it and was told it was ideal because it’s a pain killer with a very short duration of action, so it would wear off quickly when the surgery was finished. It’s amazing how the press latches onto something ‘evil’ about a drug and that becomes its sole identity (I realize that Fentanyl is dangerous because of it’s potency).

    • jes5199 says:

      You can take it orally.

  21. vV_Vv says:

    And I’m sure this is part of the story. But that just passes the buck to the next question. Abusers take the vast flood of possible chemicals and select the ones they think will feel good at raves. Psychopharmacologists take the vast flood of possible chemicals and select the ones they think will treat mental illnesses. How come the abusers’ selection process is better at picking out promising mental health treatments?

    How does it work form an intellectual property angle?

    If there is a chemical that was not developed as a drug for condition X and has already been patented for some other use or is old enough that it has no patent, and then you discover that it treats condition X, can you patent it for the novel use?

    If you can’t, then I can quite see why pharma companies are unwilling to do research on anything that they didn’t directly develop.

    • Douglas Knight says:

      You can patent a drug for a novel use, but it is pretty rare. Prescriptions don’t seem to be considered patent infringement, so doctors can prescribe the generic drug for the new use (I’m less sure if pharmacists can make the substitution). But if the new use has a different dose, that can be a barrier trapping people on the expensive drug. The only example I remember is finasteride.

      On the other hand, I have I heard of examples where people should have done this, but they didn’t, such as an old drug available in Europe, but not America, which had a new use discovered and a company did trials to get FDA approval in return for FDA-granted exclusivity of short duration. Why didn’t someone patent the new use, getting longer exclusivity?

    • Fractalotl says:

      MAPS (the Multidisciplinary Association for Psychedelic Studies) has formed the MAPS Public Benefit Corporation to oversee the Phase 2 studies and Phase 3 clinical trials for MDMA-assisted psychotherapy for PTSD.

      My understanding is that they’re basically acting as a non-profit pharmaceutical company for this purpose, which is unusual!

      http://mapsbcorp.com/

  22. rahien.din says:

    I think you’re overinterpreting a case of selection bias.

    Pharmaceutical companies are searching for very precise therapies, but druggies are seeking the opposite. If the brain is a car, pharmaceutical research is aimed at picking the lock on the door. Druggies are just the grizzly bear that tears your car door off to get at your sandwiches.

    Sure, if the door is torn off, you might get a better look at the lock so you can know how to pick it, but that doesn’t mean that the druggies are really doing it better. In fact, they’re not even doing the same thing. Self-medication does not even mean “taking a substance for its beneficial medical effects.” People self-medicate with all kinds of things that have no beneficial effects whatsoever, often purely for the sheer avoidance value. So druggies have merely selected chemicals for their effective psychologic potency.

    Because selecting chemicals for their effective potency is a source of some information, that’s where we are focusing a drunkard’s search. This induces a selection bias and we should recognize it as such, even while acknowledging MDMA and ketamine as successes thereof. It is precisely wrong to conclude “because drunks sometimes find [their own keys, someone else’s keys, spare change, something at all] under streetlights, maybe the people looking for their own keys in the park are doing something wrong.”

    MDMA is especially pertinent, as no reasonable person would expect a chemical precursor to an obsolete hemostatic drug to have any beneficial psychopharmacologic effects, much less the double-serendipity that we have observed. If anything, that is evidence that focusing on the limited menu of known recreational drugs is to embrace a potent streetlight effect. Instead we should be casting a much wider net in our search for the next psychiatric drugs.

    I wonder if you have overinterpreted this because you’ve conflated “things that get you high” with “things that treat mental illness,” and that possibly because you’re lumping all mental effects together. It may be better to consider skew cases of serendipity. What if we had discovered, instead, that MDMA cured heart failure, treated malaria, or stabilized osteoarthritis? What if, after 80 years of using a chemical as an inert biochemical solvent, we discovered it had potent antiseizure, antimigraine, and mood stabilization effects? These would be / are wondrous, but wouldn’t / don’t seem nearly as unsettling or weird or discouraging. You would just chalk them up to the staggering complexity of human biochemistry.

    Edit: minor clarification

  23. Dan Fitch says:

    Maybe a case for James C. Scott’s mētis?

  24. Forge the Sky says:

    Drugs of abuse are ones that smack the brain really hard in some direction or other. They do something. So find the psychiatric illness that’s treated by smacking the brain in that direction, and you’re good.

    There are drugs that smack the brain in very non-hedonic directions as well, and therefore don’t tend to become drugs of abuse. Take nutmeg for example; it sure makes the brain go funny for a while if you eat enough, but the effect seems to be mostly ‘see weird shit and feel like absolute hell for a few days.’ Wonder if there’s any hidden gems in that category that we just haven’t bothered looking at because the initial reaction is so bitter.

    Anyways, overall I think most psychiatric issues are far to complicated to address with a handful of specific pharmacological agents, except as a sort of temporary fix or brute-force symptom resolver. We’ll likely only make strong progress once we figure out how to recalibrate the many tiny inputs from the rest of the body that help govern brain processes. Many tiny calibrations, not one big one.

    Currently the only way we have to that is ‘try to fix up your diet and lifestyle, maybe add some probiotics and get outside’ in an attempt to compensate for the multitude of ways the modern environment and a poor lifestyle might be making things worse, but that only goes so far – both because, hey, mental illness existed back in the day too, and also not everyone seems to be able to make strong lifestyle changes.

    • Deiseach says:

      Drugs of abuse are ones that smack the brain really hard in some direction or other. They do something. So find the psychiatric illness that’s treated by smacking the brain in that direction, and you’re good.

      Yeah, well when I was drinking for the depression, that was smacking my brain around good and ‘handling’ the depression but it wasn’t doing my liver any favours, and I don’t think you intend to go the route of “so smacking your brain around with booze works and never mind that you’re also hammering your liver into submission and possibly collapse”.

      • carvenvisage says:

        I think the OP needs more argument/explanation why these drugs are expected to work great.

        As a regular reader, I’m like, “well ok if you say so it’s probably true”, but I don’t know if you would have that reaction otherwise or if it’s a good one.

        hmm, ok well actually I have next to zero qualms about that reaction, but *structurally* it doesn’t seem ideal to have the argument relying on ‘probably these will turn out to be great, now assuming that they do, why were people idiots for not discovering it sooner?’, without a super solid explanation why you’re fairly confident they will turn out that way.

        _

        Seperate topic, bit of a left turn off a cliff: what’s wrong with a bit of liver damage? You say it ‘handled the depression’. If the main cost was a bit of liver damage, isn’t that pretty good?

        _

        My model of alcohol problems is that usually it’s the final rather than decisive cause of problems. -That people who are depressed, desperate, etc, are much more likely to turn to leaning heavily on drink, so leaning heavily on drink looks worse than it is (in a vacuum) because it usually starts off on a downward trajectory (or very steady low basline).) Like, people will say ‘look what the drink did to him’, but I think a lot of the time it’s more like ‘look what the drink didn’t do for him’, because that guy was in serious trouble anyway.]

        That might be exactly the case that usually matters in real life, but I’m not sure that that holds for the scenario Scott is talking about.

        • Deiseach says:

          Seperate topic, bit of a left turn off a cliff: what’s wrong with a bit of liver damage? You say it ‘handled the depression’. If the main cost was a bit of liver damage, isn’t that pretty good?

          One of my aunts died of cirrhosis of the liver due to decades of abusing alcohol. Drinking at at a level that handled the depression were leading down that path (when a routine liver function test came back with slightly elevated levels of a couple of indicative enzymes, I took that as a sign to knock it off). Even before you get to cirrhosis, fatty liver disease is not great.

          It wasn’t “occasional glass of something now and again”, it was “you’ve reached or exceeded the recommended weekly amount of units in two days”.

  25. GregQ says:

    Abusers take the vast flood of possible chemicals and select the ones they think will feel good at raves. Psychopharmacologists take the vast flood of possible chemicals and select the ones they think will treat mental illnesses. How come the abusers’ selection process is better at picking out promising mental health treatments?

    Well, because if the abusers kill themselves, or fry their brains, or become permanently addicted to some dangerous substance, no one cares, or even notices, but if big pharma, or even little pharma, does that to someone while looking for a new drug they get sued out of existence.

    • Deiseach says:

      if the abusers kill themselves, or fry their brains, or become permanently addicted to some dangerous substance, no one cares, or even notices

      (a) True, in that if someone is facing jail or has fucked up their life via addiction, there’s not really much interest in “yeah but I used to be depressed before I started taking this”

      (b) Not so true, in that cases like Leah Betts did get a lot of publicity (and crikey, talking about E makes me feel old, since I remember when it started taking off as a party drug for raves back in the 90s – it was even used as a plot device in an episode of “Inspector Morse”). Ironically, a lot of damage was caused by water intoxication – because people were dancing for hours on E, they would get dehydrated, so the advice from the “use drugs responsibly” campaigns was to make sure to drink lots of water. Then people started drinking too much water/too much in a short period and this caused the harm (there were actually complaints of clubs which hosted raves jacking up the price of bottled water to ludicrous levels in order to make up for the money they lost on alcohol sales – people on Eezer Goode didn’t drink, they just wanted to dance and hug and cosmic love, man).

      (Music videos like the above, and remembering what it was like first time round, are part of why I’m finding it very hard to take “ketamine and MDMA as SRS SIKIATRIC MEDICATIONS” seriously. Though thank goodness the late 80s psychedelics revival in music and 90s acid house were short-lived).

      • GregQ says:

        Yep, Leah Betts got a lot of publicity.

        Now, how much publicity would a medical research company get after frying people’s brains with experimental drugs?

  26. Meredith L. Patterson says:

    > I’m a little suspicious trying to calculate the odds of a single chemical having two forms, one of which is a really exciting analgesic, and the other of which is a really exciting antidepressant, by two different mechanisms.

    Most biomolecules have two forms. That is literally what chirality is. Any time you read about some molecule having an L-enantiomer and a R-enantiomer, there’s a possibility that one of those forms does something and another form does something else.

    Sometimes that “something else” is “nothing interesting.” Racemic citalopram, otherwise known as Celexa, is a reasonably good antidepressant. Its successor Lexapro is the L-enantiomer of citalopram only. Presumably on a hunch that R-citalopram wasn’t doing anything interesting with respect to depression, Lundbeck (original manufacturer of racemic citalopram) decided to trial the L-enantiomer only and got a “new” drug out of it.

    But it’s certainly common for both enantiomers to do something noticeable, even to the same system. As one non-pharmaceutical example you can find on Wikipedia, the L-enantiomer of carvone is in spearmint, the R-enantiomer is in caraway, and this distinguishes them with respect to smell.

  27. currentlyinthelab says:

    Oh goodness this can be frustrating.

    Multiple drugs have been invented during the time-frame of the 50’s-80’s that also increase typical self-reported human happiness, in a measurable effect where absolutely everyone knows they are not taking placebo, in methods similar enough to ketamine and MDMA. There are even examples of pharmaticual companies that have produced these drugs with the explicit purpose of creating an antidepressent.

    If you look at the list of Schedule 1 and 2 drugs, you will find plenty of of the above examples there. I’m absolutely serious about that.

    I guess a good deal of what’s readibly discoverable about these drugs (beyond reverse engineering the brain and and emotive generatoin from physics) has been discovered, and simply turns out that drugs based off of these simply tend to get banned anyways.

    This isn’t so much medicine and depression determing what is legal and illegal, but culture,tradition, some legitimate addiction worries, and that giant state of human affairs we call politics. Whether or not banning those drugs was a good decision is a debate beyond the scope of normally-sized comments.

    As a very important aside. What do you mean by depression? There are multiple tests used for *depression* and one one test a sedative makes you more depressed, and on another it makes you happier. Its even logically possible to create a pill with a given set of effects, that reduces ones depression score without having obvious effects on typical understandings of depression.

  28. Error says:

    it suggests we chose the wrong part of the tradeoff curve…A drug that makes you feel extreme side effects for a few hours – but also has very strong and lasting treatment effects – is better than a drug with few side effects and weaker treatment effects.

    When I was much younger, I got put on Accutane for severe acne — not the kind that makes you embarrassed to be seen, the kind that seriously fucks up your body and leaves permanent scars. I was at a higher dose and for a longer treatment regimen than typically recommended. The drug gave me crippling depression and suicidal ideation, and both lasted a couple of years.

    I was discussing it with a friend earlier today, and realized that it might actually have been worth it. The drug did do the job it was supposed to. The cure was permanent and the (significant) side effects were not. I don’t know if I would do it again, but I would like for more drugs on the dangerous-but-highly-effective end of the tradeoff spectrum to exist.

    • carvenvisage says:

      I’m having trouble imagining how that could be worth it. Was it really severe acne?

      Are you also thinking something like “crippling depression and suicidal ideation toughen you up and make you appreciate life'”? (which imo can be true, but anthropic principle means it’s not as simple as that)

      • Error says:

        No, I don’t buy the toughening up narrative. I meant it in the simple sense of “right now, I prefer having taken it to not having taken it.” Of course, I’m saying that at a time when the passage of twenty years have dulled the memory, but I still enjoy the benefits. I might not have had the same opinion if I’d thought about it at age 20. It wasn’t until many years later that I learned the depression was likely a drug side effect rather than just Being Me.

    • carvenvisage says:

      severe acne — not the kind that makes you embarrassed to be seen, the kind that seriously fucks up your body and leaves permanent scars.

      sorry I’m illiterate

  29. Michael Arc says:

    A PHARMA CEO recently told me that CBD was the most exciting pharma of the 21st century period.

  30. MB says:

    Maybe one explanation is that many psychiatrists do not directly experience the effects of mental illness or of the drugs their patients take. Thus, it is hard for them to tell exactly what and how is working. It may be hard for any person to explain his or her internal mental state to another person, let alone if the person is under the double influence of mental problems and of some novel drug — and unhabituated to it.
    It’s also possible that many existing drugs are good and work well, but that higher doses are needed. Also, it’s possible that such higher efficacious doses would have visible side effects in some number of patients, which would make many doctors reluctant to prescribe them (especially if off-label). Certainly drug addicts wouldn’t care too much about these issues or try to sue their drug dealers.
    Also, it’s possible that many drugs that work well would have the side effect of making patients feel really good, perhaps unnaturally so — like alcohol, morphine, etc. — and even create addiction. Doctors of a more puritanical bent, who believe in the redeeming value of suffering or whatnot, might then be against their use.

  31. pontifex says:

    A normal dose of cough syrup (aka Dextromethorphan) is also pretty good for occasional insomnia.

    I wonder how different the 20th century would have been if psychotherapists had gotten LSD, Ketamine, et al. legalized as psychiatric treatments. Maybe we would have a lot fewer depressed and mentally ill people, but a lot more really, really weird people?

  32. mlogan says:

    “And maybe when a psychiatric drug is discovered by people who weren’t looking for it, what this looks like is a few random people trying it, noticing it feels good, and turning it into a drug of abuse.”

    I know this is a distraction from the point of the article, but the tone and assumptions here really bug me. First, people (including me) take drugs for a variety of different reasons other than “it feels good”. For instance, my few experiences with psilocybin were transformative about the way I think about the world and myself and nothing whatsoever to do with partying or “getting high” or whatever. Second, the term “drug of abuse” is a loaded term that seems to impute a quality (“being of abuse”) to a substance that has no such intrinsic qualities. Yes, some people abuse MDMA, but the abuse lies in the interaction between the person and the substance.

    This may seem like quibbling, but I think these attitudes manifest themselves in harmful unquestioned assumptions in the medical establishment. Specifically, it seems to be taken for granted that if MDMA or ketamine or psilocybin is shown to have useful clinical effects, it would be *even better* if a new substance could be synthesized that had the same benefits, but without being hallucinogenic or otherwise strongly psycho-active. But without a good reason for why it is so important to avoid the strong psychoactive effects, time and money spent searching for such substitutes is wasted.

    If the potential of these drugs pays out, the hesitance of the establishment to even consider them for so many decades means that millions of people have suffered needlessly. Let’s not perpetuate the attitudes that led to this.

  33. Worley says:

    I’m no expert, but my understanding is that before receptor chemistry was known in detail, the way drugs were discovered was by dosing rats with randomly synthesized chemicals and then checking if anything “interesting” happened to the rats. With psychiatric drugs, you pretty much have to use humans for the first screening. That makes it really, really hard to screen tens of thousands of compounds, so you’re likely to check only compounds that have a relatively high probability of doing something useful, which pretty much means analogues of things that are known to be effective.

    The hippies have the advantage that they don’t have to get their experimental designs past ethics review committees. But even they tend to explore analogues of things that are known to be effective …

  34. johnsonmx says:

    Drugs like MDMA and Ketamine seem to influence the brain’s core attractor basin. Drugs which pass pharmacological review are specifically screened against addictiveness and thus are implicitly screened to avoid messing with the brain’s attractor basin(s).

    Lots of problems will involve attractor basin dynamics, thus lots of problems will be untreatable with conventional drugs, and treatable with drugs that are often abused (which are abused precisely because they push attractor basin dynamics in a pleasurable direction).

    More here: http://opentheory.net/2017/05/why-we-seek-out-pleasure-the-symmetry-theory-of-homeostatic-regulation/

  35. wintermute92 says:

    A drug that makes you feel extreme side effects for a few hours – but also has very strong and lasting treatment effects – is better than a drug with few side effects and weaker treatment effects.

    I sort of wonder if this is a huge part of the missed search – researchers simply didn’t consider this side effect profile.

    Most of our psychoactive drugs either have side effects you experience at all times during use (appetite changes) or perhaps permanently (SSRI sexual dysfunction). A few have limited post-active side effects, like the hangovers for alcohol (not counting the dehydration component). Few to none have a big upfront cost with lasting benefits.

    I see a few other comments outlining drugs that do have this effect, like Accutane and chemotherapy. But notably, those are cures. Accutane in particular is distinctive for being the only decisive acne cure, but having such wretched side effects that it’s a last resort.

    Psychoactive meds aren’t expected to be curative. I’ve never heard people talk about finding a drug that would “cure anxiety” or “cure schizophrenia” the way they talk about “curing acne”. And most of the time, that seems to be accurate. But ketamine looks like a cure for depression, at least in the semi-permanent sense that chemotherapy cures cancer. I think a lot of people would eagerly schedule one shitty Saturday instead of spending years on treatments with mild but perpetual side effects.

    Is it possible that part of the issue is just failing to look for cures, or countenance the serious side effects that we can accept when issuing cures?

    • rahien.din says:

      Is it possible that part of the issue is just failing to countenance the serious side effects that we can accept when issuing cures?

      Ketamine isn’t a cure for depression in the way that Accutane is a cure for acne. It’s a symptomatic treatment. Its effects wear off.

      Unless temporary respite of your depression somehow permits other things to cure it, ketamine does not even facilitate a permanent remission.

      ETA: mumble mumble something about mosquitoes mumble mumble…

      Also, how can I fail to point out that the type of reasoning you describe is utilized all the time in medicine. Antibiotics, almost every surgery, and almost everything that happens in the ICU are all exchanges of temporary harm for permanent benefit.

      • wintermute92 says:

        Fair enough on ketamine. I don’t think it alter my point, though – it remains short term symptoms with long term remission.

        Also, how can I fail to point out that the type of reasoning you describe is utilized all the time in medicine.

        I’m fully aware – which I thought my examples of other medicines made quite clear?

        I cited acutane and chemo because they’re drugs with long term curative effects on humans, where antibiotics don’t act (positively) directly on your body and surgery isn’t a drug. The goal was to give the non-psychiatric examples that were closest to a psych med.

        I was specifically talking about psychoactive medications, as was Scott’s post. My entire point was that I suspected a focus on sustainable treatments instead of the acute ones common elsewhere in medicine.

        • rahien.din says:

          I might quibble with:

          long term

          But, fair points. I stand corrected.

          • wintermute92 says:

            And you’d be right to, thanks. I’d seen some pieces suggesting months or longer of improvement, but it looks like the standard results are a lot less than that. If it’s weeks, it’s probably still a clear win, but there’s obviously a duration below which the whole thing is net-negative.

  36. CheshireCat says:

    I’m currently in the process of cultivating Psylocibin-containing mushrooms in an attempt self-medicate for treatment resistant depression. I tried to enter a Ketamine trial but only made it past the pre-screening phase before they rejected me for not being depressed enough by their standards (which is a little depressing in its own right). None of the 3 other antidepressants I’ve tried (SSRI, NDRI and SMS (Trintellix)) have had any effect at all. I’ve never tried any psychoactive/hallucinogenic drugs before, here’s hoping for the best. Obviously I’m just one very anecdotal data point, but I have to say I’m looking forward to the experiment.

    If this still doesn’t work then I’m not entirely sure what the next step should be. Keep throwing darts at the medication dartboard and wait/hope for Ketamine approval, I guess.

    • herbert herberson says:

      Best of luck. Are you looking towards standard psychedelic resources to guide you, or something more explicitly therapy oriented? Do you personally know anyone who has used them, or at least knows you will?

      • CheshireCat says:

        Pretty much strictly standard psychedelic resources for now, since I’m just in the “planting the seeds” phase of the grow and it’s all mostly following guides and the like. In terms of therapy resources all I really have to go off is a handful of studies and a (frankly very impressive) body of anecdotal evidence claiming that it helped them. As for the actual event, I don’t really have any plans beyond going into it with a positive mindset, finding some quiet place in nature, and having a friend tripsit me while I let fungus take the wheel.

        I don’t know anybody who’s used them but my family and a few of my close friends know I’m going to try it. I’m lucky enough to have open-minded and supportive family and friends.

        If the venture ends up actually treating my TRD in any way, I will definitely make note of it in the comments section on this site at some point 😛 I wouldn’t want to let something this potentially significant go totally undiscussed, even if it isn’t exactly scientific.

        • herbert herberson says:

          Sounds like you’ve got a solid plan. Mostly just wanted to make sure that you weren’t going to chow down on a handful without telling anyone and sit alone in your bedroom!

          • CheshireCat says:

            Good looking out. I may be dumb in a lot of other ways but if I’m gonna do illegal, potentially mind-altering psychoactive drugs off-label to fuck with my brain chemistry, I’m definitely gonna do at least a little research beforehand haha

        • cuke says:

          I hope your experiment is a success. Please keep us posted!

          • CheshireCat says:

            I will! I’m not familiar with how people tend to use the comments here, should I just continue the comment thread here when I do, or post a new comment in the open thread closest to whenever I give it a shot?

          • Creutzer says:

            Post in the most up-to-date open thread, I’d say.

          • CheshireCat says:

            Will do.

    • Ashley Yakeley says:

      Why did you decide to grow them rather than buy them? I mean, it sounds like a fun project…

      • CheshireCat says:

        A few reasons, most to least important:

        – I wanted to be as sure as possible that the species and strain were of the type I wanted (Psilocybe Cubensis strain B+, pretty much the default psilocybin mushroom afaik) so that I could be as sure of purity and standardized dosages. Mostly for the sake of peace of mind, and whatever limited scientific rigor I’m going to pursue. I don’t relish the idea of buying from a drug dealer either, as it would probably be less safe and pleasant than quietly ordering spores online and growing them at home.

        – Because it’s fairly cheap, all things considered (<$100) — and should I find it to be effective it would be relatively easy to scale the stuff I bought for the project into creating more. An ordinary grow process should leave me at least two potential doses, and likely even more than that to do with as I see fit.

        – Because it is kinda fun? A lot of people talk about growing mushrooms as being a part of the journey, and leading to a much more satisfying experience than if they just bought some. It’s honestly a pretty cool process, and something I enjoy learning about. And I figure if that increases the likelihood that I find success, even if only by a little, then why not?

    • agmatine says:

      Just want to let you know: there are a number of ketamine clinics popping up run my legit anesthesiologists I get regular “maintenance” infusions by a legit doctor in Palo Alto (search for ketamine Palo Alto). I have a history of chronic / at times severe treatment resistant bipolar depression, and compulsively / cognitive impairments. Ketamine helps at the most acute phase the most but I started it mostly for compulsively a few months ago. I now get an infusion about once every 3-4 weeks, they use it off-label and it is extremely safe.

      I would highly recommend you try it.

      • CheshireCat says:

        Interesting, I will keep that in mind. I don’t want to take any other drugs for at least a month before trying shrooms so as to avoid potential confounding but if I’m still looking for more solutions afterward I will definitely consider it. I assume it’s not covered by insurance?

        • agmatine says:

          I am sort of wondering about the degree of your depression if you’re willing to forgo all treatment “in the name of scientific integrity” before trying a less researched form of depression treatment with no significant dosing guidelines. I totally get the self-treating part and have been there, but it confounds ME to see you accept additional suffering just to avoid confounders.

          Try the ketamine before the mushrooms. Don’t worry about waiting a month. If you’ve gotten that duration from various antidepressant recommendations, especially forget about it. They say that about Prozac and MAOIs for very idiosyncratic reasons.

          If you’re in northern CA I’d highly recommend Palo Alto Ketamine. insurance doesn’t cover it as in network but they try and get it coded so you at least get some minor reimbursement.

          Try the ketamine before.

          (And don’t give up on antidepressants I can’t speak for your situation and I am NOT a doctor but if you haven’t even tried Wellbutrin or augmented with Abilify you haven’t even exhausted the FIRST LINE.

          Look into folate, you don’t need the Rx Deplin form the OTC supplement form of methylfolate is identical. Or an MAOI, they work great and any risks are way overblown. Depression is a neurodegenersrive and life-degenerative disease do not underestimate how even a months delay is destructive waste.

          • CheshireCat says:

            My particular brand of depression is the kind of low-level deadness that’s lasted for many years (7+). It’s not particularly intense, there isn’t much variance to it and it’s gone untreated for years, a few extra months isn’t gonna hurt me. The only reason I’m trying shrooms is because it seems to be this weird version of depression that doesn’t fit any particular symptom cluster very well (dysthymia is the closest) and thus far hasn’t responded at *all* to any of the treatments I’ve tried.

            I’m not claiming to be practicing some kind of legitimate science by any stretch of the imagination. Mostly I don’t want to throw too many chemicals at my brain at the same time without a doctor’s consult. It’s a personal choice, any remotely science-y stuff that happens along the way is purely a bonus.

            I’ve tried Folate supplements, they didn’t help. I haven’t tried the “special blend” of methylfolate for people with the MTHFR enzyme polymorphism but it’s on the list somewhere.

            I have tried Wellbutrin, didn’t help. MAOIs are low on my list of priorities, I like cheese too much.

            I don’t live in Norcal, driving there would be far too much work.

            I’m sure there are similar clinics where I live but with all due respect, I have my plan and I’m sticking to it. I appreciate the concern, I really do, but I didn’t come here for life advice. I’m taking a short break from typical antidepressants to do my own thing, and if/when it doesn’t work I’ll go right back to the psychiatric flowchart, scout’s honor. I only made these comments for anyone interested hearing about in my experience.

          • agmatine says:

            I totally get it and apologies if my tone or intention came across as too advicey. I think psilocybin is an excellent choice (I have tried as well but don’t seem to get long lasting benefits from flood doses (nor do I get intense psychedelic reactions even with high doses, FWIW), my doctor suggested I try daily microdose though I haven’t been able to nail down correct dose to maintain functionality during the day while getting benefits). I wish you the best and hope you report back.

            I used liquid psilocybin, anywhere from 1-5mg of psilocybin for microdose, though I may try even lower.

          • CheshireCat says:

            No harm done!

            I find it surprising your doctor was open to psilocybin at all, let alone suggesting it as a treatment option. They sound like a keeper.

            What do you find happens when your microdose is a bit too high? And where do you get the liquid psilocybin?

          • agmatine says:

            Too high (I’m guessing around 3-5mg of psilocybin, so still far below low grade psychedelic effects) actually feels pretty good and is anxiolytic, but makes it hard to be productive. Attention suffers, reading is difficult, but no problem e.g. Driving or running errands. It doesn’t suck, it’s just not transparent. Personally I think for a case of treating a case of long standing depression or dysthymia/anhedonia a higher dose than traditional micro dose guidelines is probably more effective.

            I get it on the dark net via a well known supplier /u/TripWithScience and one little squeeze bottle is equivalent to 2g dried and seller says is roughly 9mg psilocybin.

            FWIW my doctor suggested psilocybin when I had mentioned I was interested in trying microdose LSD…probably because I also have OCD Like issues and psilocybin has been tested for that indication. He also suggested daily not every 3 days.

          • CheshireCat says:

            Interesting. I can’t say I fancy the idea of daily microdosing if it messes with my head, but if it works it works. Thank you for the info.

  37. Caelestis says:

    Nobody has a hard time telling whether they’re in the experimental or placebo group of a trial of high-dose MDMA

    This seems somewhat inaccurate. This is more of an fyi than anything, but I used to run some psychopharm studies looking into the effects of various drugs of abuse, and in one such study we gave experienced participants doses of 1.5mg/kg MDMA, 0.5mg/kg MDMA, and sugar pills, across several sessions in a randomized order. So, every person received every dose at one point or another. Some people who in the fist session received both the lower dose and the placebo (~1 in 10) definitely thought that they had received the highest dose. To be clear, both of those doses are pretty high. Another 1 in 10 (or so) people thought that they had received some other drug when they were given the highest dose, regardless of which session, which is maybe separate from confusing it with placebo, but there is definitely a lot of room for confusion here. It is maybe worth noting that people who received the highest dose first didn’t confuse the subsequent lower doses for the highest dose.

    The effects are definitely strong, but there is still room for a ‘placebo effect’, even among experience users of those drugs.

    *Edited for clarity*

    • Tedd says:

      To be clear, both of those doses are pretty high.

      100mg is a pretty mid-range recreational dose in the wild. At my weight (75kg), 1.5mg/kg would be 112mg. 0.5mg/kg would 37.5mg. 112mg is a moderate dose, but I definitely wouldn’t characterize 37.5mg as “pretty high” – that’s barely threshold.

      • Caelestis says:

        My mistake: the doses were the ones here, so it is 1.5mg/kg and 0.75mg/kg. So both would put you in a normal recreational dose range, with the 1.5mg/kg putting you on the high end for regular users based upon the chart you linked, and 0.75mg/kg putting you right in the middle there.

        I might characterize 100mg as a small single dose capsule ‘in the wild’, but most people didn’t receive that amount: many were under and many were over, depending on size. If we had a 100kg participant they would receive 150mg, which is “strong” on your chart. Obviously the whole thing is relative, but to mistake a 0.75mg/kg dose for placebo certainly contradicts what Scott said.

        Keep in mind that when people receive these pharmaceutical grade MDMA doses, they get to sit alone in a room and read some magazines or watch a movie, so there are a lot of things about these experiments that aren’t naturalistic.

  38. Psychophysicist says:

    I’m a little suspicious trying to calculate the odds of a single chemical having two forms, one of which is a really exciting analgesic, and the other of which is a really exciting antidepressant, by two different mechanisms. It sounds too much like finding some new chemical compound whose solid form is a room-temperature superconductor, and whose liquid form catalyzes cold fusion, by two totally different mechanisms.

    I think that the sort of chemistry that has this kind of thing occur fairly often, is also the sort of chemistry you need to support evolution of complex life.

    Or, just as there’s only so many fundamental ways to chemically smack the brain circuits, there’s only so many electron-cloud-shapes you can make by rearranging the same atoms.

  39. siduri says:

    Abusers take the vast flood of possible chemicals and select the ones they think will feel good at raves. Psychopharmacologists take the vast flood of possible chemicals and select the ones they think will treat mental illnesses. How come the abusers’ selection process is better at picking out promising mental health treatments?

    Here’s one hypothesis: at the highest level, the brain doesn’t have that many variables to affect, or all the variables are connected. If you smack the brain really really hard in some direction or other, you will probably treat some psychiatric disease.

    Another hypothesis: things that feel good are, on some level, good for you. They may also come with lots of non-good side effects, but they are doing something good and that’s why they feel good. They will naturally function as “treatments” to people who have a severe lack of whatever specific good-feeling thing it is.

    Alcohol, for instance, is so good at treating social anxiety that it’s basically “prescribed” at every party to help everyone get over their initial shyness. It has enough side effects that “just stay drunk all the time” is not an effective long term solution for chronic social anxiety, but part of the reason alcohol feels good is that it suppresses anxiety.

    Cocaine boosts self confidence. Again, probably not a great treatment for self-loathing given the side effects, but man. Someone with, I dunno, survivor’s guilt? Is probably gonna notice that it gets a lot better when they’re high on cocaine.

    Sometimes the link between the reason the drug is effective recreationally and the reason it is effective theraputically might not be so obvious. But in a case like MDMA, for instance, I think it is pretty obvious why a drug that makes you feel connected to everyone in a loving and trusting way would a) be really fun at parties and b) be a great treatment for PTSD. I would suspect the same kind of causal linkage in most other recreational drugs that turn out to have theraputic use.

    Or it might not be. I can also think of a counterargument to the theory above, which is that our current best model of ketamine suggests it’s a non-psychoactive metabolite that has most of the useful antidepressant effect. In fact, a lot of people think that one form of ketamine is hallucinogenic (and extremely effective against chronic pain) and another form (or its metabolite) is the antidepressant.

    This counterargument is strong against my hypothesis too.

  40. random.name.0815 says:

    I’m a little suspicious trying to calculate the odds of a single chemical having two forms, one of which is a really exciting analgesic, and the other of which is a really exciting antidepressant, by two different mechanisms. It sounds too much like finding some new chemical compound whose solid form is a room-temperature superconductor, and whose liquid form catalyzes cold fusion, by two totally different mechanisms.

    If that boggles your mind a bit, check your favorite paper source for material regarding ketamine and it’s possible usefulness in status asthmaticus and status epilepticus. Multiple papers on both subjects suggest that ketamine can be a lifesaver or at least a very effective augmentation to the currently established medication protocols in those lifethreatening conditions.

    Also, there are anecdotal reports (or maybe even papers by now) about a certain usefulness of ketamine in opioid withdrawal. Managing symptoms, yes, not the magic bullet. A few druggies also report that a bit of ketamine during a week-long festival will lower tolerance to psychedelics almost back to baseline, hence not having to double the required acid dosage every day. There seems to be a lot to ketamine that is intriguing on many levels.

  41. agmatine says:

    Scott, I love your psychiatry posts, but I feel like you’re missing an important point. Despite the fact that there have been no real important drugs in a new “genus”, the expansion of “species” (e.g. The proliferation of antipsychotics) means that vastly more patients will (theoretically) be able to find an *effective* medication they can tolerate over the long term.

    Lots of people can’t handle aripiprazole due to akithisia, but if the could, it would be a miracle. So cariprazine, brexipiprazole, etc. while just a new species are (theoretically) just as big of a deal as aripiprazole.

    I am surprised you haven’t mentioned the extremely long acting depot forms of naltrexone and aripiprazole. 1-2 month formulations for the most vulnerable populations had the potential to absolutely revolutionize treatment of addiction, psychosis, etc. imagine if all drug addicted / schizophrenic homeless were able to access 2 month formulations?

    In addition, the samidorphan augmented form of both buprenorphine and Zyprexa are likely to be extremely impactful and despite the fact that the primary drug isn’t new, i

    I would be extremely interested in your thoughts / clinical experience with all these drugs.