benzodiazepine withdrawal and serotonin antagonists

[Kdem]

I was wondering if serotonin antagonists could be useful for withdrawal from benzodiazepines, specifically clonazepam.

 

[dopamimetic]

Hmm, maybe I'm missing something but what's primarily helpful are glutamate and calcium channel antagonists. Things that limit excitation. Serotonin is so complicated, there's a good chance that some subtype selective drug could help but somehow I do more think of 5-ht1a agonists now, they're considered to be anxiolytic.

 

[Kdem]

It's true that the serotonin system is complicated, and it's easy to mess things up.

Wouldn't serotonin antagonists potentially be helpful by countering glutamate ? The atypical antipsychotics are generally serotonin antagonists, which is claimed to cause 'sedation'. Yeah, I know that antipsychotics are generally contraindicated in benzo withdrawal, but that was not the question.

 

[dopamimetic]

Probably this depends on which serotonin subgroup you antagonize, the 5-HT2C actually limits norepinephrine and dopamine, antagonizing it causes an increase of them. 5-HT2A antagonism and especially inverse agonism appears to be relieving and sedating if I'm right.

The antipsychotics are mainly sedating through histamine antagonism, those without H1 affinity are considered 'non-sedating'. Didn't really know that they are contraindicated (probably many doctors don't know that too unfortunately) but it makes sense because dopamine antagonism lowers the seizure threshold, and this is a no-go in benzo withdrawal.

Which serotonin receptors are linked to glutamate? This is interesting because I'm looking for something that helps with tolerance to dissociatives and rebound effects, at least for the latter a glutamate limiting agent that doesn't work by antagonizing NMDAR's and thus causing more tolerance would be of great benefit.

I've read recently that the atypical antidepressant bupropion also reduces glutamate trafficking, at least in rats. This could explain why it isn't as stimulating as it should be as a cathinone.

Maybe some of the old anticholinergics & antihistamines like diphenhydramine or doxylamine could be helpful for bento w/d? And of course memantine, this is probably the best thing that's available by prescription. Or one could taper down and switch to tiagabine, a GABA reuptake inhibitor that also raises GABA activity but by a different MOA and appears not to have dependency issues curiously.

 

[Cotcha Yankinov]

I think Trazadone is a really good option for trying to catch some sleep in this situation, it's 5-HT2A antagonism is sedating (5HT2A forms heterodimers with glutamate) as well as its alpha adrenergic antagonism (also sedative) and if I remember correctly it's H1 antagonism all contribute to its sedation. I believe it's also an agonist at 5HT1A (which is good because 5-HT1A is an inhibitory kind of serotonin though there are also auto receptors). Antipsychotics can help as well, Seroquel and risperdal come to mind (both 5-Ht2A antagonists with alpha adrenergic antagonism. Seroquel doesn't occupy dopamine receptors very much at low doses like 25mg too, and risperdal is similar. Risperdal is chemically very similar to ketanserin, which was one of the original 5-HT2A inverse agonist sleep drugs, in some models it doubled slow wave sleep.

 

[serotonin2A]

Antipsychotics and antidepressants tend to lower the seizure threshold and hence have to be used with caution in people suffering from benzodiazepine withdrawal.

 

[dopamimetic]

Is the mechanism known by which antipsychotics do that?

One theory I've made was after reading about the regulatory function of dopamine in regards to glutamate, that low levels of DA will lead to more glutamate activity and thus overall excitation (think of benzodiazepine withdrawal, here is GABA involved too but in the end it's about too much excitation happening). This could be wrong, it's quite complicated - there's a paper about NE knockout mice that were very susceptible to seizures, but this is unusually as e.g. clonidine actually prevents some and think of psychostimulant overdose.

Based on that, could the antidepressants lead to an (initial or permanent) inhibition of dopamine release by 5-HT2C activation?

 

[Cotcha Yankinov]

^interesting... Do you think a selective 5HT2A antagonist would lower the seizure threshold? Or is it more related to dopamine and the glutamate fallout of inhibiting dopamine? I think I remember something about the projections involved in Parkinson's, there are dopamine projections that keep a very excitable thalamus contained essentially, which is one of the reasons why people with Parkinson's have tremor??

 

[serotonin2A]

Many monoamine receptors are neuromolulatory and hence can influence seizure propagation. I think the suspected mechanism for antipsychotic effects on seizures is blockade of D2, alpha-1 and H-1 receptors.

 

[dopamimetic]

Hmm.. Cotcha, you probably know more about the 5-HT system than me but I wouldn't attribute seizures to 5-HT2A antagonism (or inverse agonism) now.. I had the theory that agonism could lead to partial seizures / abnormalities especially in the temporal lobe in susceptible individuals, being the cause for some psychedelic-induced psychosis (doesn't even have to be a real psychosis, temporal lobe abnormalities are linked to mystical experiences and such).

Alpha-1 would make sense, as this does increase NE. H-1, I don't know. Are antihistaminics dangerous for people with epilepsy?

 

[Kdem]

#4: references to exact receptors are hard to get.
Here is this study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430669/
And from a 'google book' (not going to type it all!) 'serotonin 5HT2a receptors increase EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release'

I'm not sure if anticholinergics are contraindicated in benzo withdrawal but I don't react well to those at all.
Personally I wouldn't want to touch high dose antipsychotics for sleep. Risperdal is a lot like haldol, and its dopamine antagonism would tend to increase w/d symptoms dramatically. Perhaps they could be used, but you would have to be very careful.
I already have muscle ridgidity and I don't think a neuroleptic would be an asset !

 

[Kdem]

#4 subtypes of serotonin receptors: clonazepam has important effect on the serotonin system and on the cholinergic system.
Changes in the serotonin transmission, serotonin receptors. Actually all sorts of secondary effects. At least partly related to its antimyoclonic action and its effectiveness against absence seizures. I could probably get some references, but that may be a bit much.

I know about motor issues, akathisia ...
Recently I ate some carbohydrate rich food in the afternoon, and the colors started glowing strongly ... No, I don't have any experience with psychedelics if you don't count this drug. I guess that was related to either blood sugar or insulin.

I've been thinking about 'fixing' the serotonin (or cholinergic) system, but I can't really find a way to do that. Except maybe by means of serotonin antagonism, but it is easy to hit the wrong things. SSRIs are way too stimulating, and sort of rewire the brain. Which would seem to interfere with a withdrawal from clonazepam.
You probably can't do much with this, but I also seem to be very sensitive to drugs hat are antagonists for the muscarinic receptors.
There is the whole theory of 'continue living normally while tapering the drug directly' (a little late for that), or the 'switch to diazepam' theory which ignores the effects of clonazepam on serotonin/acetylcholine and indirectly many other neurotransmitters, not to mention that it is a very different drug. It would be great if there were a way to fix the serotonin/acetylcholine system, it's really not just a 'GABA' issue.