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Addictive nature of Benzodiazepines/Z-Drugs identified

Lightning-Nl

Lightning-Nl

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Nov 11, 2012
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I finally came across an explanation as to why but benzodiazepines can be so psychologically addicting to some people. These studies explained the what/when/how and why of the GABA subtypes and interactions.

Simply put, Benzodiazepines causes a massive disinhibition of Dopamine regulation through binding at the alpha-1 subtype of GABA-a. Even more selective agonists (or PAM agent in this case) could, theoretically explain the adverse side-effects and addiction potential of Zolpidem. Zolpidems highly selective to alpha-1 and likely facilitates over-active expressive repression dipression exertion upon dopaminergic activity. Massive dopamine activity would explain Zolpidems hallucinations and sleep walking. I've always wondered with the amine group of the nitrogen and three carbons on the Zolpidem molecule if it has nAChR or other cholinergic activity.

Anyways, why is all of this? Well here's an excerpt from the study.

Mechanisms of Benzodiazepine Addiction (Left Image) Both inhibitory interneurons (labeled GABA) and dopaminergic neurons (labeled DA) are subject to the restraining influence of the inhibitory neurotransmitter GABA. A key difference, however, is that GABA influences the inhibitory interneurons largely via the alpha-1 subset of GABAA receptors and the dopaminergic neurons largely via the alpha-3 subtype. (Right Image) Benzodiazepines currently on the market do not interact strongly with alpha-3 GABAA receptors on dopaminergic neurons and so have no direct impact on dopamine release. However, the drugs do interact strongly with alpha-1 GABAA receptors, thereby curtailing inhibitory interneurons’ release of GABA into synapses with dopaminergic neurons. The net result is a lessening of GABA restraint on the dopaminergic neurons and an increase in dopamine release.

To prove that activation of alpha-1 GABAA receptors underlies benzodiazepines’ dopamine effect, the researchers administered a typical benzodiazepine, midazolam, to two groups of mice. The results supported the researchers’ proposed mechanism: In normal animals, the firing rate of interneurons decreased in response to the drug, while that of dopamine-producing neurons increased. In contrast, in animals that were genetically altered to prevent benzodiazepines from potentiating alpha-1 GABAA receptors, the drug had little or no impact on neuron firing.
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Now here's where things get even more interesting. After the findings of the study above we're released, another doctor decided to perform tests on the interaction between benzodiazepines and the alpha-1 subtype of GABAA. These finding found that increased alpha-1 activity caused a massive migration in AMPA receptors located on DA neurons. The expressed AMPA receptors are excitatory to glutamate, and won't actually cause any increase in dopaminergic activity, but will actually cause excitatory repression of synapse cleft surges in dopamine activity effectively suppressing dopamine activity.

Dr. Lüscher and colleagues showed that benzodiazepines induce AMPA receptor migration via the alpha-1 GABAA receptors. In these experiments, brain tissue from normal mice exhibited GluA2-lacking AMPA receptors after a single injection of midazolam, but tissue from mice with benzodiazepine-insensitive alpha-1 GABAA receptors did not. Recordings of intracellular electrical currents confirmed synaptic changes of dopamine-producing neurons in the normal mice and not the altered mice. To pin down the relationship further, the researchers injected mice with two other compounds, one (zolpidem) that preferentially activates only the alpha-1 GABAA receptors, and one (L-838417) that antagonizes these receptors. GluA2-lacking AMPA receptors were expressed in dopamine-producing neurons following a treatment with zolpidem, but not with L-838417.
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I'm looking for a study I once saw on this right this minute, but can't find it at the moment. Will update in a moment.
It appears that while glutamate and monoamine neurotransmitters are both excitatory, monoamines suppress glutamate activity in the mesocorticolimbic reward pathways, and glutamate suppresses monoamine activity in general around the nervous system. Benzodiazepines through GABAergic neurotransmission, suppress glutamatergic activity via calcified ion channel openings and negatively charged chloride ion pathways negating suppression of monoamines. Effectively causing spikes in dopamine activity due to lack of suppression of neurotransmission of glutamate. or "spikes" in monoaminergic activity.

I've yet to see a study on it but my theory is that through nAChR receptor channel activity, chloride ion and calcium ion channel manipulation and other bindings release opioid peptides and causes neurotransmission of dopamine. Speculation I can provide is that some of the antinociceptive activity of benzodiazepines caused by smooth muscle relaxation is the depressing of the muscle due to neuromusclar sedation.

Studies

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013137/pdf/pone.0015870.pdf

doi:10.1038/463743a

http://www.drugabuse.gov/news-event...nderlies-benzodiazepines-addictive-properties
 
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Zolpidem is a wierd one for sure... it causes some people to come out of comas, temporarily... [ref 2] Not what you'd expect from a sedative. (Unfotunately it's not a panacea.)

All of the individual benzos hit slightly different combinations of benzodiazepine subtypes, 'cause they're all slightly different structures, and there are something like 7 different GABA-A subunits... I thought the word on the playground was that temazepam and the triazolos (alprazolam, triazolam) are considered to be rather euphoric while demethylated benzos like clonazepam and nordazepam are sort of mute.
 
For some reason, I seem to have a lack of euphoria from Temazepam. Don't get me wrong - it's the only benzo that's even 1% euphoric, however, compared to Zolpidem - it's not euphoric at all. Zolpidem was the most addictive drug I've ever taken. For some reason - it was just overpoweringly reinforcing and I HAD to take more. Couldn't help myself.

Temazepam... not really. I've stuck to my prescribed dose of 30 milligrams for a long-time now. I only had a 'craving' (I put that in quotes because it was nothing like a craving) for it once. Otherwise, everything has been good. I wonder if the fact that I take it only 4 hours after an Adderall IR dose, if that blocks some of the 'dopamine spiking' they talked about in the studies.

Or maybe it's the 30 milligrams of DXM I take every night before bed to help with amphetamine tolerance. Either way, I've never had addiction issues with Temazepam. Zolpidem? Yeah... and by yeah, I mean I was taking 60 milligrams every day for a couple months... Couldn't help but keep raising the dose either...
 
sekio said:
Zolpidem is a wierd one for sure... it causes some people to come out of comas, temporarily... [ref 2] Not what you'd expect from a sedative. (Unfotunately it's not a panacea.)
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Ever see the movie 'Awakening' ? It's about Oliver Sachs - the man who discovered L-DOPA. He learned that patients who were in a state of total catatonia (even after they had been in comas for over 20 years) would come out of their coma's when they were given huge doses or L-DOPA. Unfortunately, these patients would return to their catatonic states after a couple months of being treated with L-DOPA, but it was a huge discovery.

That proved that there was a directly link between Dopamine deficiency and pervasive catatonic states. These specific patients all had untreated polio as children and they learned that even though they survived polio - polio had created an autoimmune defect in these patients - the immune system started attacking Dopamine producing cells and that's why these people would go into coma's.

With that being said - In different cases (such as with Zolpidem) I wonder if GABA activity is too active and/or the Alpha1 subunit is not expressed properly like it should be. Or it's possible that it could relate to the increase in AMPA receptors. Indicating vastly underactive Glutamatergic activity.

Anyways, all of that is just speculation.
 
I was prescribed triazolam for a short period of time; I remember very little as it binds to alpha-1 strongly (memory loss anyone?) and penetrates the BBB very fast. I found alprazolam to be superior. It's really hard to do a comparison because if you take large doses of triazolam you'll just forget what the fuck happened, whereas that's not necessarily the case with benzodiazepines which are relatively selective for a2/a3 such as alprazolam. Zolpidem was quite moreish for me; I remember a GP readily prescribing it at a young age. Looks like there might be something unique to zolpidem relative to tother benzodiazepines http://link.springer.com/article/10.1007/s00213-014-3457-x#page-2. This is the second one which essentially states its MOA is unknown http://jop.sagepub.com/content/24/11/1619.short.
 
My first triazolam experience (.25 mg?) involved me sitting down to watch TV, remarking that I feel funny, and waking up in bed 4 hours later. I was told that I brushed my teeth in the interim. Best blackout outcome ever!

ebola
 
Thanks.
That may explain why I have so much energy and motivation to get almost everything done while on low doses of Alprazolam. It's the same with Zopiclone.
 
Yeah, alprazolam and zolpidem definitely have a dopaminergic signature. I found them to be more usable than e.g. lorazepam. Thanks for sharing indeed!
 
Iv zolpidem is intense benzo like relaxation, strange kinda trip, not particularly overly pleasant but definitely something unique to this vs all other benzos probably even zopiclone and the other z one.

Anyone tried Dr butts alcohol replacement? Pagoclone!?
 
Tryptamite said:
Anyone tried Dr butts alcohol replacement? Pagoclone!?
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It's nice but kinda underwhelming in low dosages. I had only a small sample long ago which was pink and route insufflation. Pretty different from the Z-drugs, like a very clean anxiolysis and disinhibition without the dark and heavy parts of ethanol but ..well, pretty unique. I'd bet for some dopaminergic activity too.
 
What a loon to think it could replace alcohol even to get regulated most government and society see any "mind altering" substance as inherently wrong!
 
I have some experience(s) with this class and may have something to add but looks like a lot of great content to read up on first (what is posted here).
Love the "class" of people here at at bl... have i ever mention that? lol
 
Temazepam and triazolam produced more reinforcing behavior (maintained higher self-injection rates) among both animal and human subjects when compared to the majority of medically used benzos.

Temazepam is consistently ranked among the most problematic benzos when it comes to abuse and potential for dependence.

Dr. Ashton's Temazepam Abuse:

Benzodiazepines have been injected but at present temazepam is mainly involved. Strang et al. (1994) conducted a questionnaire survey of subjects attending drug clinics in seven British cities. Of 208 subjects returning the questionnaire, 186 had used benzodiazepines and 103 had injected them intravenously. Temazepam was the most commonly abused (149/186) and had been injected (99/103) from preparations of capsules, tablets and syrup. The severity of the addiction which can develop to temazepam is illustrated by the case of a temazepam injector who needed his leg amputated but was later admitted for a second amputation since he had continued injecting into his remaining leg. A second subject, following a leg amputation, injected temazepam gel into his eye, resulting in bilateral blindness.
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That's some serious addiction, there ^
Temazepam accounted for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary throughout Australia throughout the 80s and 90s. Pharmacists and their staff often encounter aggressive and threatening behaviour from people seeking temazepam. There were 537 burglaries on Victoria's 1200 pharmacies from 1 January to 30 August 2001, including 'ram raids' (using stolen cars to smash through windows). Temazepam appears to be the main target in many pharmacy burglaries. Temazepam is sought in 85% of all reported benzodiazepine forgeries in Australia throughout the 1980s and 1990s.
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very interesting topic. although reward and reinforcement have been shown in a few studies to occur in the absence of dopamine, they are nowhere near a strong or significant. any drug that stimulates dopamine release in the reward pathways, will almost certainly be addictive. even without the dopamine, benzodiazepines shut down most brain activity needed for consciousness, and that’s a powerful way to escape The stress and anxiety, which are a constant and major factor in our daily lives. throwing a huge spike of dopamine into the equation creates serious potential for addiction.
 
It's nice to feel a little vindicated. I hadn't seen this thread but had been asserting that it's a1 affinity that also makes nitrobenzodiazepines, Z-drugs and indeed alcohol addictive.

That's why IN 2012 I designed selective a6 ligands and found they produced all of the positive effects of alcohol BUT not the negative ones (loss of executive function, mood lability, ataxia and syncope) never mind the toxicity of alcohol itself.

It IS possible to produce dependence to an a5 PAM but it seems like it treated dependant alcohol users who had sensitized a5 receptors. They displaced reverse-tolerance with lower doses used as compared to no dependent people who, none the less could identify alcohol. Only semi-structured so not conclusive.
 
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BTW so if you design a benzo with NO a1 affinity, it's much safer (for many reasons).

But people SEEK that a1 activity - now we know why.

So pyrazolam, pyeyzolam and pynazolam having no a1 affinity were all quite different. An anxiolytic, an alcohol mimic and for want of a better term, an entactogen benzo.
 
Since BUD or benzodiazepine Use Disorder happens in only .02% of people or 2 in 1000 people I would say it high time we gave up on the idea that benzodiazepines are addictive. Very likely to cause nasty physical dependence, for sure. Addictive, no way.
 
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