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Barbiturates - StructureActivityRelationship and Abuse Potential

Snowy

Snowy

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Sep 6, 2009
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Hi!

I've been searching for a good paper or ressource for the SAR of barbiturates and potecy comparison.
I'm also interested in the relation between structure and time of onset and abuse potential.
It would be helpful if someone could provide some equvialence doses and pharmacokinetic data.
If you don't know much at all just post your favorite barbiturates and all you tried with maybe some short data about them
(doses, time it lasted, time of onset, etc.)...

PS: I have seen some SAR data about them but rather abstract information without any real-life examples as foundation.:\

Thank you for any information about that. :)
 
Here is some information from the book Pharmacology and Therapeutics, 6th ed, (1965).


Generally you need two alkylgroups on the 5 position, and they need to be ethyl or longer. If you use two identical groups I think you can go up to dibutyl and retain activity, but if you keep one group as ethyl or allyl and vary the other, you can get up to pentyl or higher. Branched groups will make them shorter lasting.

I also got an excellent paper on barbiturate SAR/pharmacology, but only a paper copy. Look it up:
Shideman, F E, "Sedatives and Hypnotics II: Barbiturates" in the book Pharmacology in Medicine, 2nd ed, (1958), pages 159-179
 
faster onset, shorter duration = more abuse potential with barbs, and pretty much all cns depressants. that pattern holds with pretty much all drugs of abuse, though.

There are also the cyclo substitutions, phenyl increases duration enormously. cyclohexenyl IIRC, is very short, however, though I see the only listed above is a 1-methyl 1-cyclohexenyl.

If you go 1,1-dimethyl you've got an antagonist, IIRC.

Secobarbital was one of the most enjoyed barbs because of it's fast onset and short duration. I don't think people would enjoy those with "anaesthetic durations" as listed above because it'd just be too much redosing. Then again, crack is well enjoyed and AFAIK, that's just redosing. However, you redose too soon on these and you fall asleep and never wake up again. you redose on crack too soon and you see black helicopters.
 
Sorry to say, I disagree with the 0.1g hypnotic dose for pentobarbital. That should be changed to 0.2g which is what secobarbital and amobarbital is quoted as a hypnotic dose. Pento is in the same category as these two yet it gets 0.1g as a hypnotic dose. Sorry, no go.

I should know because a couple of years ago I was able to get hold of TWO mL of "green dream" (equivalent to ~600mg pento). I measured everything to get 100mg and it only just touched me, but when I got it up to 200mg I got smashed. I'd say 100mg is the threshold where it will start to affect you. 50mg is nothing and won't do diddly squat except maybe take the edge off my nerves. 200mg is where it's at. Pentobarbital should be intermediate acting and not short acting, because pentobarbital takes longer to hit you than secobarbital, not as long as amobarbital but still takes much longer than secobarbital, which hits you in about 10 minutes. Pento takes, for me, a minimum of 30 minutes. I weigh around 95-100kg give or take 1 or 2kg, with a 25%+ body fat composition so maybe that weakens it as barbiturates are fat soluble and that is how they work by penetrating fatty tissues in the CNS...BUT they also penetrate other body fat which can dissipate them and weaken their effects.

That said, I took the other 400mg a week or so later and ended up sleeping for nearly 2 days and vomited a few times during the 2nd day and the hangover was nothing to sneeze at either.

My words of wisdom - do not mess with this stuff, and I can assure you I will never touch it again - unless I intend to take a lethal dose...I don't like it, for me it wasn't euphoric at all and didn't do anything that alcohol couldn't do...suicidal overdose (ie. 10+ grams) aside it's practically useless to be honest. I prefer alcohol, alcohol has a warmer sedation whereas the pentobarbital was like a cold dead sedation, almost anaesthetic-like, with a very nasty hangover effect that lasted me nearly 2 days.
 
Thanks for all the posts! :)

Since the potency of most barbiturates doesn't differ much data about onset and more precise data about duration and half life in a comparable manner would be nice.

Are there some experienced barbiturate users around? Would be nice to post some experiences :-) ...
 
Half life, even on the short duration ones is quite long. There's something about them rapidly entering the brain and then being sequestered in fatty deposits throughout the body, I don't understand it to be honest, but I find it interesting nonetheless. I never paid much attention to the pharmacokinetics, I was always more interested in how they bind in the brain.
 
Don't the shorter-acting, fast-acting, more euphoric and potent barbiturates have higher plasma protein binding, with the slower, longer and least euphoric have a very low protein binding?

I think the way a longer-acting barbiturate works is kind of a built in extended release due to distribution in the body. AFAIK short acting ones just goes straight to the head more.

Out of the thousands of possible barbiturates, is secobarbital, pentobarbital and amobarbital really the most abusable ones?
 
Quite possibly. There's a fairly specific set of alterations that produce the quick onset relatively short duration that's desired. IIRC, something like 2500 have been synthesized and characterized. There's a reason these were picked. It wasn't for the recreational effects, but rather because they happened to have the qualities that just happen to yield the enjoyable effects.

The thiobarbiturates are another area but they're even shorter duration IIRC. Thiamylal looks neat.

Don't consider IV'ing those, though. I imagine they smell bad and if it's like zopiclone, you'll 'taste' or 'smell' that right through your blood.
 
L-37%20fig%206.jpg


Here's graphs of thiopental concentration in various tissues after intravenous administration. The concentration in the brain peaks rapidly due to fast crossing of the BBB and then goes down quickly when the drug is redistributed to muscle and fat tissues. The actual hepatic elimination has a half life of 24h, so waking up from the anesthesia is caused fully by the redistribution.

The more lipophilic the barbiturate, the sharper the peaking in brain levels, and the more euphoria and abuse potential. Things like secobarbital are absorbed so quickly that the redistribution phenomenon is seen even after oral administration.

PS. As an academic curiosity, even selenobarbiturates have been considered as sedative-hypnotics... ( http://books.google.fi/books/about/The_Selenobarbiturates.html?id=NQqoHwAACAAJ&redir_esc=y )
 
I don't see anyone having made any tellurium-based barbs... I'm sure they smell too fucking bad!
 
I would assume so. However, I see that thiourea is odorless... That seems quite strange. Regardless, I'd be shocked if seleno- and telluro-urea were. Perhaps they might not be as bad as they sound.

The fact that a garlic-like taste is apparently an actual known side effect of IV thiobarbiturate use (I was just guessing when I posited this above) doesn't lend well to the possibility of seleno-compounds doing well. A clandestine chemist would do well to stick to the oxo and thio compounds. You'll have a hard time selling your l337 drugz if you smell like rotting dog farts.

Whenever Thio, Seleno and Telluro- compounds come up, I'm always reminded of this blog post, and the comments that follow it:
NSFW:
Things I Won't Work WIth: Thioacetone
Posted by Derek
My recent entries in this category have, for the most part, been hazardous in a direct (not to say crude, or even vulgar) manner. These are compounds that explode with bizarre violence even in laughably small amounts, leaving ruined equipment and shattered nerves in their wake. No, I will not work with such.

But today's compound makes no noise and leaves no wreckage. It merely stinks. But it does so relentlessly and unbearably. It makes innocent downwind pedestrians stagger, clutch their stomachs, and flee in terror. It reeks to a degree that makes people suspect evil supernatural forces. It is thioacetone.

Or something close to it, anyway. All we know for sure is that thioacetone doesn't like to exist as a free compound - it's usually tied up in a cyclic thioketal trimer, when it's around at all. Attempts to crack this to thioacetone monomer itself have been made - ah, but that's when people start diving out of windows and vomiting into wastebaskets, so the quality of the data starts to deteriorate. No one's quite sure what the actual odorant is (perhaps the gem-dimercaptan?) And no one seems to have much desire to find out, either.

There are sound historical reasons for this reluctance. The canonical example (Chemische Berichte 1889, 2593) is the early work in the German city of Freiburg in 1889 (see page 4 of this textbook), which quotes the first-hand report. This reaction produced"an offensive smell which spread rapidly over a great area of the town causing fainting, vomiting and a panic evacuation.". An 1890 report from the Whitehall Soap Works in Leeds refers to the odor as "fearful", and if you could smell anything through the ambient conditions in a Leeds soap factory in 1890, it must have been.

The compound shows up sporadically in the literature until the mid-1960s, when several groups looked into thioketones as sources of new polymers. The most in-depth analysis took place at the Esso Research Station in Abingdon, UK, where Victor Burnop and Kenneth Latham got to experience the Freiburg Horror for themselves:

"Recently we found ourselves with an odour problem beyond our worst expectations. During early experiments, a stopper jumped from a bottle of residues, and, although replaced at once, resulted in an immediate complaint of nausea and sickness from colleagues working in a building two hundred yards away. Two of our chemists who had done no more than investigate the cracking of minute amounts of trithioacetone found themselves the object of hostile stares in a restaurant and suffered the humiliation of having a waitress spray the area around them with a deodorant. The odours defied the expected effects of dilution since workers in the laboratory did not find the odours intolerable ... and genuinely denied responsibility since they were working in closed systems. To convince them otherwise, they were dispersed with other observers around the laboratory, at distances up to a quarter of a mile, and one drop of either acetone gem-dithiol or the mother liquors from crude trithioacetone crystallisations were placed on a watch glass in a fume cupboard. The odour was detected downwind in seconds."
Now that's a compound to be taken seriously. How do you work with something that smells like hell's dumpster? Like this:

"The offensive odors released by cracking trithioacetone to prepare linear poly(thioacetone) are confined and eliminated by working in a large glove box with an alkaline permanganate seal, decontaminating all apparatus with alkaline permanganate, eliminating obnoxious vapors with nitrous fumes generated by a few grams of Cu in HNO3, and destroying all residues by running them into the center of a wood fire in a brazier."
So there you have it - just install a fireplace next to your hood (what every lab needs, for sure) and remember that, in a thioacetone situation, fogging the area with brown nitrogen oxide fumes will actually improve the air. (This is from Chemistry and Industry, 1967, p. 1430, if you need more details, and I hope you don't).

http://pipeline.corante.com/archives/2009/06/11/things_i_wont_work_with_thioacetone.php




On a more relevant note, in the US, derivatives of barbituric acid are controlled drugs. However, does this include the thio derivatives?
 
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Hamm, I believe thiobarbiturates are close enough in terms of pharmacological action (and obvious structural similarity) that they would be considered "analogs" by every jury.

I would expect that you can name the non-abusable barbiturates on one hand, kind of like non-abusable fentanyls.
 
What about primidone? It's a pro-drug for phenobarbital that's AFAIK isn't a controlled substance, or at least it hasn't been regarded as one.
 
I think that's because it's not very extensively converted, very "dirty" side effects-wise, and phenobarbital is considered to be about as recreational as placing a sandbag on your head.
 
THC2LSD said:
Don't the shorter-acting, fast-acting, more euphoric and potent barbiturates have higher plasma protein binding, with the slower, longer and least euphoric have a very low protein binding?

I think the way a longer-acting barbiturate works is kind of a built in extended release due to distribution in the body. AFAIK short acting ones just goes straight to the head more.

Out of the thousands of possible barbiturates, is secobarbital, pentobarbital and amobarbital really the most abusable ones?
Click to expand...

First there aren't thousands of barbiturates and second yeah seco, pento, and amo are among the most abusable barbs. But there are others that are highly recreational and are at least as good, maybe even better than amobarbital. Seco and Pento are the top 2. But Butabarbital is a very very good one, probably better than amobarbital. Other decent ones are Allobarbital, Hexobarbital (this one is supposed to be really good), Butallylonal, Brophebarbital, Heptabarbital, Talbutal, Hexethal, and Thiamylal. Those are the ones I can think of right now. There are a few others though.
 
^AFAIK there is a couple thousand barbituric acid derivatives that have been synthesized. Did think butabarbital might be about like amobarbital based on it's onset and half-life. Maybe they fortunately didn't get the notoriety of amobarbital to warrant CII status?
sekio said:
I think that's because it's not very extensively converted, very "dirty" side effects-wise, and phenobarbital is considered to be about as recreational as placing a sandbag on your head.
Click to expand...
It does some nasty shit, but phenobarbital or any barbiturate isn't exactly Tylenol. I wasn't think of primidone proper, more like something with 2-pentyl in place of phenyl. It seems that in humans about 15-25% of primidone is converted into phenobarbital and it's not that toxic relative to barbiturates. Might not be that great if the conversion is very slow, a la phenmetrazine vs. phendimetrazine.

Were all those unmarketed barbiturates tested in humans? Or tested in addicts using ARC ratings? I was wondering if there might have been some that did not stand out medically in terms of onset, distribution, toxicity, duration, anticonvulsant action or hypnotic/sedative effects, but somehow felt pretty damn good compared to most. Perhaps it merely wasn't marketed because of so many similar drugs. Shit LSD and Librium were overlooked at first.

I haven't heard much about the individual isomers of barbiturates. Only some shit in pigeons and a few in mice. http://www.ncbi.nlm.nih.gov/pubmed/3367297 It's kind of hard to extrapolate the effects in pigeons to humans. Seems the more effective isomer is S. Could one isomer have lower toxicity or be the more euphoric one in humans?

Wasn't there some designer barbiturate that turned up in Japan? I think it was one that would still be illegal in the USA.
 
For the O.P. I have always had a taste for barbiturates but due to availabilty its easy to keep under control, I have started using barbs for the past 2-3 years so I wish I had more experience but this far I've had the obvious phenobarbital, benzobarbital, butabital and amobarbital which i've had most experiences, with pheno the second most.

The equivalency for barbs as I know it is
100mg phenobarbital = 100mg amobarbital = 100mg secobarbital; the difference is in the onset while pheno has a 2-3hr onset amobarb’s onset is about 40min-1hr
Butabital and benzobarbital are a bit different; benzobarbital 70% of its weight is phenobarbital (common in Russia) therefore
100mg benzobarbital = 70mg phenobarbital
100mg Butabital = 30mg-25mg phenobarbital

I feel 100mg pheno is the same as 100mg amo with the exception that pheno has an onset of 2-3hrs while the formers onset is 40mn-1hr, which is what I think makes amobarbital so much more euphoric.

Favorite barb from my list is amobarbital hands off, for me 50mg is enough to relax and even go to sleep. I've taken as much as 250mg in one setting and as little as 25mg. Snorted it burns too much and it takes away form the high though it makes it stronger (1.5x bioavailability wise) the onest is much quicker about 15-25min, i've only used this MOA on 2 occasions.

Orally amobarbital, kicks in about 45min and fuly takes over in 1hr, depending on the situation it always produces an intense relaxation on the body as well as the mind which is slowly taken over by a distinct euphoria (similar to alcohol but different). Small doses of 50mg-75mg are enough for relaxation and sometimes even sleep, however most times I take 100mg, or 150mg, rarely 200mg. With 100mg you feel a true muscle relaxation in your entire body and your mindstate. You feel really hypnotic in your way of thinking (if you watch a show you get drawn in by it, things become more interesting you feel a bit 'floaty' and easy to go along with things to the point of 'nodding' out or sleep).

The euphoria can best be described as hypnotic in that when you lay your head down and watch tv for example, the more you focus on the tv the more drawn you get in the hypnosis, sounds feel drowned out, as you sink more into your mind and become more introverted you feel like your mind is cushioned with velvet. It feels euphoric simply to think esp. as you go from though to thought there is a process of analysis in which you are completely relaxed, very content and at peace with the world. The more you increase your dose the more pronounced the relaxation and euphoria though I think anything over 200mg is a waste unless you have a huge tolerance.

When taken for sleep if you take it and go lie on you bed until it kicks in, its very easy to go to sleep due to the hypnotic effect wich basically draws/pulls you very easily. It gives a heavy/guarenteed, restful sleep and you wake up refreshed with no residual effects, other than maybe a bit relaxed. In many aspects they beat benzos out of the water and are better in every way, also barbs dont have the amesic side of benzos. In this way they beat benzos out of the water and are better in every way, also barbs dont have the amesic side of benzos, here is no impairment in memory and the cognitive impairment is much less as well. It gives a warm euphoria with a very noticeable relaxation throughout your body in all your muscles, the relaxation is superior to that of alcohol or benzos and gives off euphoria without much impairment esp in comparison.

After 100mg it really depends what you want to acheive since most people including myslef consider 100mg both a recreational dose for mornings as well as a great dose for sleep but you may go up to 200mg or 300mg with the same effects described with more intensity

Taking barbiturates to potentate other drugs or to come off stimulants is a different story though if they were more readily available they would take the place of benzos when using opioids (personally never exceed 50mg), alcohol however is the one substance in particular that significantly potentates barbiturates to a sometimes dangerous level, benzos as well (say one takes 4-6mg lorazepam a day, with barbs 1mg is enough). Last but not least, the best, surest and perhaps the safest way to come down from a stimulant comedown is not benzos nor alcohol but barbiturates b/c with benozs sleep doesn’t always come easily and its not a sure thing, while barbiturates seem to take care of the physical component and mental aspect all the time. For anymore questions PM me.
 
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I'd agree with muie, but also would like to add that my experience with pentobarbital (also called Nembutal) was a strange one.

100mg one day, I would feel a bit relaxed. 100mg another day, I'd feel dizzy and lightheaded and not really with it. Then 100mg on another day I would not feel much relaxation at all and would in fact sometimes get agitation and start ranting to myself out loud. I went through 30 x 100mg Nembutal over the course of a few months, taking note of the effects. The effects range from 1 to 10 on an arbitrary scale. Sometimes it works, sometimes it doesn't. It's hit and miss. I took 200mg and just felt drunk, and the greatest irony is I couldn't fall asleep even if I felt so relaxed because I was talking to myself like a maniac - that was until I took 90mg mirtazapine and that eventually got me to sleep - and it works well with Nembutal because it seems to synergise with the H1 receptor antagonism that mirtazapine is famous (or infamous, if you will) for.

Does anyone know what's behind these mixed reactions? Barbiturates are not my cup of tea, but I do believe they're the strongest sleep drugs because for me they've rarely failed to get me to sleep, especially the pheno (funny that), and of course, let's not forget, they are PERFECT for suicide, which is why the fast acting ones are no longer around - well, not to most people anyway.

Phenobarbital to me is actually stronger than pentobarbital despite it's slower onset and it's reputation as being weak is really not justified. It's damned strong stuff regardless of how your typical junkie thinks of it. If I take 240mg phenobarbital it begins to take effect in 30 minutes - seriously, that's all it takes to start hitting me, and within an hour I could be falling asleep on it. If I take 100mg pentobarbital, it takes effect in 15-20 minutes, but pento doesn't seem to really slam until about 90 minutes after I've taken it, whereas pheno slams me in 60 minutes and it slams hard as a brick wall. The only difference between these two drugs is the gradient of effect. They both get you to the same point, but the gradient is different. With pheno it's a slow onset then all of a sudden WHAM, you hit a brick wall and you are on your arse! With pento it begins it's effect almost immediately and initially it's weak but then ramps up gradually until you feel the stronger effects. Maybe that's why junkies prefer the gentler gradient of pento (if I say so myself). Maybe I'm not your typical cookie-cutter insomniac. I'm a dyed-in-the-wool insomniac, I never had trouble sleeping as a child, but as an adult getting to sleep can be a fucking nightmare.

Pento lasts about 8-10 hours, makes me feel a bit sleepy for about an hour or two after waking up. Pheno lasts a day and sometimes will kick my arse for 2 days. Pento is a very strong anxiolytic but not a very strong hypnotic for me. Pheno is both a strong anxiolytic and an enormously strong hypnotic. I don't understand why a drug that is classed as weak works so well for me - it's more reliable at knocking me on my arse than Nembutal. I know junkies prefer a quick strong effect, but pento doesn't give me such an effect unless I drop like 300mg and then it's lights out for about 6 hours and waking up with a very shitty hangover and wishing I had died - not unlike alcohol - where I want to lash out at anyone who irritates me, with feelings of paranoia and anxiety coming on hard once the drug wears off and then spend much of the day complaining about the weather, people, certain things, etc and being a pain in the arse to myself and everyone around me. I never got that with pheno. Strange but true. Pento hits quickly and gently and gets nice and strong as it goes from the 30 minute mark to the 60 minute mark, but it stops bluntly and brutally. Pheno is slow to hit, and starts to hit at 30-40 minutes, but when it gets to the 60 minute mark it seems to start hitting like a freight train, sudden and forceful, but it tapers off nice and gentle, and doesn't leave me with a hangover that makes me want to do nasty things.

Pentobarbital is like a straight 45 degree line, constantly increasing in effect to the peak, whereas phenobarbital is like a parabolic curve that seems to do nothing for a while then starts to ramp up like crazy.

BTW as far as toxicity is concerned, I think hexobarbital was the most toxic commonly available barbiturate, and not pentobarbital as many have claimed. Phenobarbital is less toxic due to it's lower lipid solubility but if enough of it is taken an overdose can easily be fatal.
 
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