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Disulfiram for anxiety, new research

Jabberwocky

Jabberwocky

Frumious Bandersnatch
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Currently approved and prescribed to deter alcohol use by preventing the metabolization of alcohol, new research into the pharmacokinetics into disulferam shows a significant drop in anxiety in mice comparable to benzodiazepines.

www.frontiersin.org

Frontiers | Disulfiram Produces Potent Anxiolytic-Like Effects Without Benzodiazepine Anxiolytics-Related Adverse Effects in Mice

Disulfiram is an FDA approved drug for the treatment of alcoholism. The drug acts by inhibiting aldehyde dehydrogenase, an enzyme essential to alcohol metabo...
www.frontiersin.org www.frontiersin.org

This is on mice, though.

"Disulfiram is an FDA approved drug for the treatment of alcoholism. The drug acts by inhibiting aldehyde dehydrogenase, an enzyme essential to alcohol metabolism. However, a recent study has demonstrated that disulfiram also potently inhibits the cytoplasmic protein FROUNT, a common regulator of chemokine receptor CCR2 and CCR5 signaling. Several studies have reported that chemokine receptors are associated with the regulation of emotional behaviors in rodents, such as anxiety."

An old study from the 80s (on humans) seems to suggest it might improve *or* worsen anxiety in active male alcoholics:


interesting... I'm planning on asking my doctor for this when I see them in a few weeks. I think it could benefit me in a large way for anxiety, or, if only to stop drinking.
 
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@n3ophy7e I'm curious if you had any opinion on this as you're the only person I know who has taken it

did you find any use for it other than preventing you from relapsing?
 
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Negentropic said:
@n3ophy7e I'm curious if you had any opinion on this as you're the only person I know who has taken it

did you find any use for it other than preventing you from relapsing?

hope you and the kiddo are well :)
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Interesting......
I haven't noticed any difference in my anxiety one way or the other as a direct result of taking disulfuram. Over time there is a decrease in my anxiety due to remaining sober, but not as an effect of the medication itself.
 
Just read the wiki on this stuff... interesting, I didn't realize that's what antabuse was. I wonder how often people give in and drink while on it? Sounds like it can be very dangerous to do so.
 
Xorkoth said:
I wonder how often people give in and drink while on it? Sounds like it can be very dangerous to do so.
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I was wondering that as well.

The chemistry is as follows:​

  • Normally your liver turns alcohol into acetaldehyde1, then acetic acid
  • Acetic acid is harmless, but acetaldehyde is one of the main causes of hangovers
  • Disulfiram stops the whole process at the acetaldehyde stage, allowing it to build up in your system
This means that you can wind up with five to ten times more acetaldehyde in your body than normal. And the result is—you guessed it—five to ten times the hangover.

This effect can start almost immediately, and continue until the alcohol has completely left your system.


So I guess it doesn't mean alcohol would build up in your system in a dangerous way, you just get a super hangover... and it's exponentially more toxic to your liver.
 
The wiki lists the side effects of drinking on it, and they include respiratory depression. I guess acetaldehyde is centrally active too, and can cause memory loss and impairment. But hard to find receptor binding info or really much info at all on its effects.
 
this wiki is interesting...

Acetaldehyde is also found in tobacco smoke, cannabis smoke, plastics, automobile exhaust, and naturally in the environment... it's everywhere and a common organic compound apparently

I wonder if disulfiram also makes you susceptible to environmental factors or weed... probably not as alcohol likely produces 1000x that which is in the environment?

The More You Know Kitty GIF
 
I wouldn't worry about envinronmental acetaldehyde, a unit of ethanol is 14 grams, which assuming complete metabolic conversion to acetaldehyde, would yield about 13.5 grams of acetaldehyde per drink consumed. This is an overstatement likely as other enzymes can convert acetaldehyde to acetic acid, such as catalase which is found in the brain.

Acetaldehyde is pretty noxious and is irritating/aversive at the tens to hundreds of parts per million level. It would be deeply unpleasant to achieve toxic systemic levels through envinronmental exposure.
 
Xorkoth said:
Just read the wiki on this stuff... interesting, I didn't realize that's what antabuse was. I wonder how often people give in and drink while on it? Sounds like it can be very dangerous to do so.
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There was an Alcoholic who would drink while she was on Disulfiram. She obviously preferred Alcohol/ Acetyldehyde over sobriety.

She would drink till she died at a quit young age, she would be about 65 by now. But this was the kinda Alcoholic that would piss, shit and vomit in her house. Walk around the hood naked and lived between empty bottle's.

Actually a very nice lady, I was a kid back then and we talked from time to time. She was a friend of my mom.
 
In the UK at least, doctors are NOT keen on prescribing disulfiram to alcoholics. Goodness alone knows how much more damaging acetaldehyde is to the body compared to ethanol 9acetic acid is easily removed as a salt). There is a species of mushroom called 'Tipplersbane' (coprinopsis atramentaria) which was discovered to contain the amino acid coprine. A fragment of this namely 1-amino-1-cyclopropanol is supposed to be a much safer alternative to disulfiram, but since treatment of alcoholism has moved away from medicines that MAKE one ill, it never reached market.

I believe that the first step in an alcohol antagonist has been developed. Ro15-4513 (a Flumazenil analogue) blocks the effects of high doses of alcohol.

I spent 5 years and DID design a 'drunk' pill. That was the problem - couldn't emulate 2 glasses of wine. 5 years later I found out why, 2 years later and the design is almost complete.
 
Fertile said:
In the UK at least, doctors are NOT keen on prescribing disulfiram to alcoholics. Goodness alone knows how much more damaging acetaldehyde is to the body compared to ethanol 9acetic acid is easily removed as a salt). There is a species of mushroom called 'Tipplersbane' (coprinopsis atramentaria) which was discovered to contain the amino acid coprine. A fragment of this namely 1-amino-1-cyclopropanol is supposed to be a much safer alternative to disulfiram, but since treatment of alcoholism has moved away from medicines that MAKE one ill, it never reached market.

I believe that the first step in an alcohol antagonist has been developed. Ro15-4513 (a Flumazenil analogue) blocks the effects of high doses of alcohol.

I spent 5 years and DID design a 'drunk' pill. That was the problem - couldn't emulate 2 glasses of wine. 5 years later I found out why, 2 years later and the design is almost complete.
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You are actually busy developing a drug that help's alcoholism.

Keep up be d.i.y. or in lab it can only profit mankind. But I wanna know is this one or the other.

Kratom for example works great against alcohol dependence, there is a transition fase that might be annoying but once on K one feels much better.
 
No, it's designed to be a compound which has all of the positive effects of alcohol without being toxic. But most certainly if people mixed it with other drugs, it COULD pose a danger and so any compound that reverses it's effects WILL be free.
 
right? the aversive nature of ethanol is part of why most mammals aren't on it 24/7
 
Interestingly, we noted that the most significant receptor in alcohol dependence is the α1 subunit of the GABAa receptors. It's also responsible for many of the negative effects (mood lability, syncope, amnesia among others). The same site as Z-drugs act on. The novel ligands are all α5 selective.
 
Allylbenzene said:
Disulfiram also inhibits dopamine β-hydroxylase (DBH) which is an enzyme that converts dopamine to noradrenaline.
The result is, generally speaking, increased dopamine and reduced noradrenaline.

Disulfiram's main MOA which is ALDH inhibition increases the formation of Tetrahydropapaveroline which might act as a dopamine reuptake inhibitor and potentially interact with the opioid system.
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That nature paper shows that THP has anti-addictive properties from tamping down dopamine synthesis, and lowering dopamine levels (which decreases the strength of cravings). I buy that one more as it’s less than 20 years old (the third paper is quite loose, as they claim it interacts with opioid systems because it potentiates morphine, and that combo can be blocked by naloxone, despite showing naloxone-insensitive antinociceptive effects).
 
Skorpio said:
(the third paper is quite loose, as they claim it interacts with opioid systems because it potentiates morphine, and that combo can be blocked by naloxone, despite showing naloxone-insensitive antinociceptive effects)
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Fair point! Interestingly it seems that THP could contribute to the endogenous synthesis of morphine in humans. This might be a factor in Disulfiram's effects and implies that other ALDH inhibitors would do the same thing - eg diallyl trisulfide from garlic, diethyl disulfide from durian (ref1, ref2).

Parkinson’s disease, L-DOPA, and endogenous morphine: A revisit

It is twenty years since the publication of a clinical report indicating an approximate 20 fold enrichment of morphine, codeine, and the benzylisoquinoline (BIQ) alkaloid tetrahydropapaveroline (THP, norlaudanosoline) in the urine of Parkinson’s disease patients receiving L-DOPA replacement therapy, as compared to naive healthy controls.
...
These collected results provide putative evidence that endogenous morphine and codeine are synthesized in vivo utilizing L-DOPA and/or DA via the well characterized Pictet-Spengler condensation product THP [40–42] as an early intermediate precursor molecule. A later report demonstrated stereoselective expression of the (S) enantiomer of THP in human brain, thereby providing additional support for a regulated pathway of de novo synthesis of endogenous morphine via enzymatic O- and N-methyl transferase conversion of (S)-THP to (R)-reticuline.
- https://doi.org/10.12659/MSM.883259
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