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Thread: Tolerance related question, chlormethiazole bromethiazole

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    Tolerance related question, chlormethiazole bromethiazole 
    #1
    Been thinking this one over for a while now, and it doesn't seem like it should be the case, seems like one of those 'just wait, it's on it's way sneaking up on you' kind of things, what with, aside from a few really mild herbs, nothing like a GABAergic free lunch, at least not for long.

    Anyhow, I've been watching it, and even going without a few days, which given the short duration of action would mean any physical withdrawal would show itself relatively soon after a last dose, if a physical dependency was present, as opposed to say, something like barbital, nitrazepam, phenobarb, other crazy-long half life benzos taking days or even close to a week, perhaps even more, if someone were at an equilibrium dose with regards to plasma level saturation.

    Chlormethiazole IS of course lipophilic as hell, given how FAST the stuff acts. There are only three drugs I can compare to chlormethiazole base orally, for speed of oral onset, one is ether, the other ethanol and the last, is no other than the analog of chlormethiazole where the bromine atom is used as a bioisosteric replacement for Cl. So tissue redistribution to fat reserves perhaps? not that I've got many of those to speak of, never have had probably never will either. I seem to have one of those lucky metabolic rates in that sense, the one where you do get a free lunch, or at least, you might pay for the food, but only financially, without ending up as an overfed, overworked chemist slowly going to seed with every bite of a big greasy double cheeseburger.

    As far as my biochemical responses to downers of the GABAergic types, also, I am a self-confessed 'hard head', only exception has been propofol when used for surgical induction. Generally a dose of something like chlormethiazole/bromethiazole, or a benzo, or even both, that would flatten most people, along with my opioid pain meds, and leave them out cold, I just seem to require quite a lot of GABAa agonist for a given purpose. I've stood standing after 4-5x192mg chlormethiazole and after having, in increments, IIRC something like 70-75mg oral nitrazepam, and even then, to put that into perspective, I'm pretty sure I could have run a familiar lab synthesis with hazards, such as say, submitting a molecule to the Boveault-Blanc reduction using sodium in anhydrous ethanol, and not had any problems related to capacity to perform the reaction, or run a distillation of white phosphorus, something that was a known procedure, not needing to learn new techniques unfamiliar on the fly but that demands a high degree of caution, care and finesse in handling the reagents. Although I wouldn't likely have tried something like developing a new de-novo 10-step stereoselective synthesis of a natural compound, something like reducing an oxime to an amine, B-B style, would have been as much problem as going for a cigarette before the chemistry equipment were to be broken out, or something like a borohydride reduction or borane reduction that would need to have existing techniques adapted to take the pyrophoricity of borane/diborane into account, pretty confident that in the state that followed from that chlormethiazole/nitrazepam combination, that I could have gone through the mechanical process itself and isolated the product, whatever it might have been, at the end, made sure it was clean and compared favourably enough with otherwise on lowest dose of just chlormethiazole (3x192mg/d, although its been as much as 3-4x that on some weeks, several in a row at times, even months)


    I'm just hard as shit to knock down. NOT intended as a boast, indeed, I find it quite undesirable. The margin of safety is of course not a bad thing, but at the same time, it does mean, that with more inherent resistance to the acute, short term post-dosing effects of such drug, more substance is required to gain the desired level of effect and this is done with greater difficulty, meaning all it is, is less fucking well economical on my prescriptions, my time, my reagents and gas mask filters get used at a faster rate.

    Anyhow, the reason I take chlormethiazole (and bromethiazole sometimes) is prescribed, the chlormethiazole that is, the brominated homolog is of course an in-house affair, is because I have a seizure issue, with myoclonic and atonic (paralytic) seizures. Which of course, for a chemist, are something I cannot permit to affect me whilst working with anything much more toxic or corrosive than 1M HCl, or saturated NaCl brine, as losing muscle control and throwing say, a flask of some vicious little bastard of an interhalogen compound either across the room, or dropping it over myself, would be a disaster. The non-med supplied stuff is of course purified carefully, by vacuum distillation of the freebase product AND of intermediates, once aqueous workup of toxopyrimidine removal and destruction has taken place, starting of course from the obvious thiamine. Its active, it works just as well as chlormethiazole from a heminevrin cap from the pharmacy, or an equivalent dose of course, would work in preventing seizures, so its not the synthesis itself thats making me wonder, especially as the VAST majority of my intake of chlormethiazole is prescribed, just a lot easier to make rescue packs for when an aura hits or the beginnings of a seizure that breaks through happens, than ask the doctors meant to be implementing the 'ad hoc, when it'll be required refilling them, just because too many doctors think 'must be freakishly addictive'

    Weird thing is that even over years, years and years of repeated daily dosing, thrice 192mg calc. as chlormethiazole base, I can stop it cold turkey and get NO withdrawal effect, psychological or physiological bar an increase in seizure frequency if the drug I take to maintain prophylaxis against having seizures is no longer active in my system, the original problem is there to unmask itself and show its ugly face, but this should be understood as my returning to untreated, pre-treatment baseline rather than an amplification of seizure tendency beyond what the reasoning for my taking chlormethiazole anis to begin with (when I'm using it medically, rather than the much more occasional here and there rec. dose. For that, I use my own stuff, so I'm not left short, using either chlor- or bromethiazole depending which thionyl halide happens to be less precious at the moment. Have considered switching to use of PCl5, as its easier for me to make some than to make SOCl2, or buy SOCl2, given I have rather a gluttonous surfeit of red phosphorus, or white, if I desire it, having gotten a money off deal from my contact in exchange for getting twice the mininum order (1kg min order for red phos), for economy reasons, and because, well, y'all know what 'three letter porcine agencies' types think of private citizen chemists having the luxury of nice big stocks of red, white phosphorus, acyl halides and anhydrides, alkylating agents, reducing agents, even alkali metals aren't approved of very much, although given they can't very well ban potassium and sodium compounds from the private individual, seeing as how one must intake both to maintain life itself, and Li is available from batteries if thin films are desired, or cheap as pellets and strips, so anything more or less. But SOCl2 is one of those I have to go through the proper channels, from a private individual's point of view, which are probably not the same as 'proper channels' from a chemical company's point of view (and no, they don't involve theft on my part of said reagents, I am a respectable private chemist and pharmacologist, not a thief)

    Or possibly PCl3, and of course either PBr5 or PBr3 for the brominated homolog, but I've not yet got round to testing these for the halogen reaction of the final intermediate when proceeding via B1, which too, makes a most economical proposition given its ease of availability and low price, although of course, removing toxopyrimidine carefully is essential. That said, I do take great care, knowing that it is a convulsant poison via vitamin B6 inhibition, to make sure my precursor methylthiazole-2-ethanol is worked up to a proper and thorough quality before it is ever used. And I cannot, bar the taste of the stuff going down, find any fault with my products, they are active, and no impurity has ever been detected which followed through after a vacuum distillation of the chlor/bromethiazole base. Its just that necking a portion of either of them as just freebase, nothing else, off of a teaspoon, it does leave rather a burning and kinda funky taste in one's mouth, but thats inherent in the drug; and nothing I can do to the nature of the drug will make it less icky to take a mouthful of freebase chlor/bromethiazole.

    Have yet to test the phosphorus based chlorinating/brominating reagents, or to add a trifluoromethyl group or difluoromethyl group in place of a halogen. Which is likely the next analogs to be explored, homologation of the alkyl chain, and addition of multiple halogen atoms, as a 3,3,3-trifluoropropyl or isopropyl group, nitrating it, cyanation, pentafluorosulfanylation,that kind of thing, basically to exhaust the potential of thiamine before moving on to having to construct the corresponding oxazole ring system itself by hand. Not out of laziness, but I may as well cherry pick all the low hanging fruit before climbing the tree, no?


    So, why, even with both increased antiseizure med use of chlormethiazole, and time to time, higher dosed recreational use of chlormethiazole or bromethiazole, over a period consisting of at least three years, probably five or even more; do I have no physical dependency? GABAergic drugs are notorious for it, and I've watched my ass like a hawk with a scatological obsession, you might say, because ending up physically dependent on a short-intermediate acting barbiturate-site agonist GABAergic is certainly not something I desire or will permit to happen.

    It just seems, along with bromethiazole, to have REALLY low tendencies to forming physical dependency in me. Why would this drug, with the mode of action the two have, as AMPA-antagonism-less barbs, more or less, correlate with a low dependence potential considering a daily pattern of use over years?
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    #2
    The pseudohalides may have been studied. Just remove the -Cl and paste the SMILES into Reaxys and search for similarity.
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    #3
    Good idea, TY.


    What do you make of the weird tolerance related features of the original, though? Because, well, for a drug that might as well be a barbiturate with it's AMPA receptor affinity lopped off, a tolerance/dependence 'free lunch' is pretty much the textbook polar opposite of what one ought to expect.
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    #4
    Do you have data if the weird low dependencies/rebound are of your body as a special case, or is it a common feature of clomet?
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    #5
    It seems somewhat equivocal. And of course one has to bear in mind, I'm not a rat
    https://www.ncbi.nlm.nih.gov/pubmed/3463157

    https://www.ncbi.nlm.nih.gov/pubmed/3463158


    Two somewhat contradictory reports (rat)

    I really can't be sure if there's just something weird about me (well I can. there's ten tons of weird, but no idea whether that particular brand of fucked up is due to personal makeup or if it is the drug itself)

    The first study used what IMO would be a fairly large dose for a rat. And in the case of continual IV infusion at a lower dose such as in the latter study, that would nullify any pharmacokinetic effects.

    The short half life alone doesn't make sense, look at ultrashort-duration benzos, like alprazolam, triazolam, and mid-duration ones (IMO the duration of action of a single dose of chlormethiazole is comparable to lorazepam.)

    But, duration alone doesn't fit for the answer to the lack of tolerance. A benzo would have left me physically dependent for sure. Lorazepam did, once.

    Difficult to get too much data though, given chlormethiazole is fairly rarely used clinically, and AFAIK the brominated analog isn't at all, I've never read of anyone else trying it.
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    #6
    As ,mentioned above, it'd be very hard to find people prescribed this drug, It isn't even listed in the BNF for seizure control, somehow I ended up with it for that reason (and it works well, and if the shit hits the fan, it works within minutes, or less,at least as fast as the onset of a sufficient amount of spirit liquor to get someone shitfaced, It'll bring me out of a seizure bad enough for someone else to have to put the capsules in my mouth, and as soon as they open after swallowing, I'll be fine again, barring post-ictal shitty (to borrow a phrase from a friend of mine who too, suffers seizures, in her case due to Rett's syndrome+ something like MERFF or MELAS), but as soon as I feel the stuff burning in my throat, moments later I'll be able to move again, speak again etc.

    But I've been taking it for years, and unfortunately I know what barbiturate WD is like, yet I can abruptly cease use of chlormethiazole or bromethiazole and not suffer any WD at all. I just don't get how such drugs can NOT cause a nasty as hell WD. Can't get data for the brominated homologue since i've never known anyone else to have taken it, and medical use of chlormethiazole here, its viewed as a drug of last resort. I know of nobody else RX'd it or who have synthesized it for their own use off-RX.
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