The anxiolytic effect of anti-histamines (alimemazine)

[ScaredFirstTimer]

Hi, I remember trying to look this up earlier, but after a while of googling, I didn't find a complete answer.

I currently take 5-10mg of Vallargan (alimemazine) sparingly here and there for insomnia. I've also noticed that it's got a pretty effective anxiolytic effect, so I've started taking it earlier in the evening, especially if I'm going out and anxiety is to be expected (currently suffering from MDMA induced anxiety++). Can someone please explain the mechanism of the anxiolytic effect of anti-histamines like this? I remember reading that some anti-histamines are antagonists for several serotonin receptor subtypes as well. Is this the main mechanism by which the anxiolytic effect is achieved?

 

[ScaredFirstTimer]

Anybody with ANY knowledge of first gen anti-histamines here?

 

[endotropic]

Hydroxyzine is the most commonly used 1st gen antihistamine for anxiety. If you read the wikipedia page for that drug they claim that the 5-HT2A antagonist activity explains its anti-anxiety effects, citing this book (free online): http://books.google.com/books?id=qu...+serotonin&pg=PA196&hl=en#v=onepage&q&f=false

The problem is, that book doesn't say anything 5-HT2A contributing to the anti-anxiety effect! Considering that multiple first-gen antihistamines have similar anti-anxiety effects, it seems to me that the antihistamine activity is the important action.

 

[lolwhatzdrugs]

Hydroxyzine is the most commonly used 1st gen antihistamine for anxiety. If you read the wikipedia page for that drug they claim that the 5-HT2A antagonist activity explains its anti-anxiety effects, citing this book (free online): http://books.google.com/books?id=qu...+serotonin&pg=PA196&hl=en#v=onepage&q&f=false

The problem is, that book doesn't say anything 5-HT2A contributing to the anti-anxiety effect! Considering that multiple first-gen antihistamines have similar anti-anxiety effects, it seems to me that the antihistamine activity is the important action.

So it is H1 inverse agonism + CNS penetration that gets you the desired effects?

From the hydroxyzine article:

Unlike hydroxyzine, cetirizine is not reported to appreciably cross the blood-brain barrier, but it has been reported to be associated with dystonic reactions as well as sedation. Therefore it has a narrower spectrum of effects, making it an effective antihistamine but removing some or all of the anxiolytic and analgesic-sparing properties, but it may cause dystonic reactions and drowsiness in some patients.

However the cetirizine article says:

Cetirizine crosses the blood–brain barrier only slightly, reducing the sedative side-effect common with older antihistamines.

This is a big difference between "not reported to appreciably cross" and

Loratadine is also an inverse agonist of H1 (just like the other two mentioned), and it says that it can't cross the BBB at all.

So a few questions I have, how well does cetirizine cross the BBB compared to hydroxyzine and loratadine? What are all threes bind affinities to H1 and other receptors? If they're extremely close and all influence the same receptors (I'm sure these two things happening perfectly or very closely are unlikely, maybe there are better candidates for this?) can their efficacy be correlated then by their CNS effects? I assume that CNS action is required for such effects, and therefore their ability at this effect would indeed correlate nicely.

Hydroxyzine has shown to be as effective as the benzodiazepine drug bromazepam in the treatment of generalised anxiety disorder.

At a good deal safer than bromazepam, and as far as I know less addictive (Are H1 reverse agonists or antagonists dependency forming? Is there rebound effects upon cessation? I don't think they are on either effects, but if so it would be the latter), it seems like this should be used more as a first line drug. It must be due to the very intense hypnotic effect of these drugs that they're not used in that manner. Diphenhydramine is a good deal stronger IMO at producing hypnotic effects in me than temazepam/etizolam/clonazepam ever was, hell any benzo.

 

[endotropic]

So a few questions I have, how well does cetirizine cross the BBB compared to hydroxyzine and loratadine? What are all threes bind affinities to H1 and other receptors? If they're extremely close and all influence the same receptors (I'm sure these two things happening perfectly or very closely are unlikely, maybe there are better candidates for this?) can their efficacy be correlated then by their CNS effects? I assume that CNS action is required for such effects, and therefore their ability at this effect would indeed correlate nicely.

At a good deal safer than bromazepam, and as far as I know less addictive (Are H1 reverse agonists or antagonists dependency forming? Is there rebound effects upon cessation? I don't think they are on either effects, but if so it would be the latter), it seems like this should be used more as a first line drug. It must be due to the very intense hypnotic effect of these drugs that they're not used in that manner. Diphenhydramine is a good deal stronger IMO at producing hypnotic effects in me than temazepam/etizolam/clonazepam ever was, hell any benzo.

Compared to hydroxyzine cetirizine hardly crosses the BBB at all. Central H1 antagonism causes drowsiness and I've never felt a lick of drowsy after taking Zyrtec. So without even reading any literature I feel fairly confident saying that cetirizine doesn't reach the brain in appreciable concentrations with normal dosing.

And for some more concrete evidence, this paper compares the three drugs in question, listing hydroxyzine > loratadine > cetirizine: http://www.ncbi.nlm.nih.gov/pubmed/17180728

As far as correlating H1 affinity with central effects, I don't think enough work has been done using 1st generation antihistamines (other than hydroxyzine) as anxiolytics to correlate H1 affinity with anxiolytic effects. If you want to correlate H1 potency with sedating effect I'm sure you can find that info though.

This paper has some great descriptions of psychiatric use of hydroxyzine: http://www.ncbi.nlm.nih.gov/pubmed/23557449
Case 2 describes a teenager who was switched from clonazepam to hydroxyzine due to concerns of dependency with the former. Her anxiety was well controlled for 6 months before she stopped treatment, with no mention of withdrawal/rebound effects, although they mention complaints of mild sedation. That seems like a fairly typical scenario from what I've read.

 

[lolwhatzdrugs]

Awesome, thanks for the response! Zyrtec is one I've never taken - non-drowsy ones I've taken are 2nd/3rd generation ones so glad to hear some actual subjective input.

 

[MeDieViL]

Very interesting to see this one pop up, i rediscovered it myself months ago and have been using it to test its effects when combined with stimulants.

I def agree that it has anxiolytic effects, just like hydroxyzine it may be mediated by the 5ht2a antagonism.

 

[lolwhatzdrugs]

Very interesting to see this one pop up, i rediscovered it myself months ago and have been using it to test its effects when combined with stimulants.

I def agree that it has anxiolytic effects, just like hydroxyzine it may be mediated by the 5ht2a antagonism.

You talking about alimemazine? It doesn't appear to be available OTC in the US, and the other phenothiazine antihistamine I recognize (promethazine) is prescription only.

I wonder if inverse agonists would work just as well if that is the method of action like this one https://en.wikipedia.org/wiki/Nelotanserin (a selective inverse agonist, created for insomnia).

http://pubs.acs.org/doi/abs/10.1021/jm100479q

Recent developments in sleep research suggest that antagonism of the serotonin 5-HT2A receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT2A receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT2A receptor binding affinity, high selectivity over the 5-HT2C receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (δ power) and sleep consolidation at doses as low as 0.1 mg/kg.

Anyone have journal access?


Also this seemed interesting
5-HT2A antagonists in psychiatric disorders
http://www.ncbi.nlm.nih.gov/pubmed/12054060

Several lines of evidence support a role for serotoninergic (5-HT) system abnormalities in the pathogenesis and treatment of several psychiatric disorders. This review summarizes information about the association between the 5-HT2A receptor gene and its relevance to schizophrenia, tardive dyskinesia, major depression, suicidality, anorexia nervosa and obsessive-compulsive disorder. Evidence is presented that implies that selective 5-HT2A antagonists may be considered useful in investigating the role of 5-HT2A receptor function and in the treatment of psychosis, and possibly alcohol and cocaine dependence. Additionally, findings are reviewed on the importance of 5-HT2A receptor antagonism in contributing to the therapeutic effect of several clinically effective and potential atypical antipsychotics as well as several antidepressants. In conclusion, the ability of selective 5-HT2A receptor antagonists to interfere with the heightened state of dopamine activity without altering basal tone, suggests that these drugs possess antipsychotic activity and may provide the basis for new therapies for psychosis and drug dependence, in addition to contributing towards a more complete understanding of 5-HT2A receptor function.

Emphasis mine, what does the antagonism of this receptor likely play in drug dependence? I know this has gotten a bit off topic from antihistamines, but if that is the method of action that these antihistamines work on, I suppose it isn't off topic.

Edit:

Found this thread, http://www.bluelight.org/vb/threads...gonism-do-(more-specifically-for-depression-) I needa read through it I suppose

 

[endotropic]

The idea is that 5-HT2A antagonism limits excess dopamine release in cortical areas, therefore it should make abused drugs less rewarding. That theory was based on the fact that a lot of the newer antipsychotics are potent 5-HT2A antagonist and they have less (dopamine mediated) extrapyramidal side effects compared to the first generation drugs. More recently I've seen people arguing that the 5-HT1A partial agonism action of those drugs is more important than the 5-HT2A antagonism as far as limiting dopamine, so I'm not sure how well the 5-HT2A antagonist story is supported.

 

[lolwhatzdrugs]

But is this more for drugs of abuse that more generally effect dopamine (which effect DAT and dopamine release) like cocaine and methamphetamine? I know dopamine plays a little bit of a role in opioid addiction but I think that it is minimal compared to the rush of snorting cocaine.

 

[endotropic]

But is this more for drugs of abuse that more generally effect dopamine (which effect DAT and dopamine release) like cocaine and methamphetamine? I know dopamine plays a little bit of a role in opioid addiction but I think that it is minimal compared to the rush of snorting cocaine.

There's debate whether 5-HT2A antagonism has a noticeable effect on dopamine level at all, so I have a hard time imagining how that effect will put a dent in the surge cocaine causes. Drugs like opiates and nicotine indirectly increase dopamine activity, so maybe a 5-HT2A antagonist can limit those less robust downstream effects? It certainly wouldn't eliminate an opiate buzz entirely, but maybe limit the rewarding effects?

Personally I don't think 5-HT2A antagonists will be effective addiction treatment for any class of drug (except 5-HT2A agonist psychedelics I guess), the effect is just too minor (if it exists).

 

[Tone303]

CYPROHEPTADINE HAS BEEN OVERLOOKED !!

I hope you all dont mind if I reply to an old thread -- i just wanted to bring it to everyones attention that its retarded to used any other 5-HT2a antagonizing anti-histamine except for cyproheptadine

its the ONLY ONE that leaves alone dopamine and has low affinity for the "Good" 5-HT-1a receptor -- its binding profile charactoristics have some how passed up the medical and psychiatric community of the world, who instead gives seroquel, hydroxyzine, trazadone and others for the explicit purpose of antagonizing 5-HT2a, when right in front of their noses there exists something far-more selective for 5HT2a and a few other 5-HT subtypes, yet LOW AFFINITY FOR 5-ht-1a and Dopamine !!!

This is so important i logged in and posted, and i never bother posting anywhere except lunatic outpost sometimes.

PLEASE make psychiatrists aware that its retarded to target 5-HT-2a with dirty unselective drugs when CYPRO exists !!!!

Its a long-time custom now for psychiatrists to use 5-HT-2a Antagonists off-label for disorders other than schizo-spectrum; and yet the psychiatric science community has not noticed that Cyproheptadine would be most-ideal for this purpose !! LOOK at this Profile and compare it to all the other drugs they use to antagonize 5-HT2a!! remember, its "Bad" to antagonize 5-HT1a and Dopamine when you are only looking to target 2a.... LOOK -- its 59 nm for 1a, yet 2.2 and less for other 5-HT's and over 100 for D1 and D2 !!

Not that Cyproheptadine can be catagorized as a "Great Help" to anyone, but still, This Image and a print out of this forum post should be on the desk of every psychiatrist on Earth

Try to find me just ONE other drug that has such high affinity for the Excitotory 5-HT subtypes yet much lower affinity for the inhibitory 5-HT-1a and the important D1 and D2 receptors......WHy the hell are psychiatrists giving everyone seroquel, trazadone, hydroxyzine and such when Cypro can be tried first to see if it works, then resort to those others secondly!?!?!

 

[Neithman]

CYPROHEPTADINE HAS BEEN OVERLOOKED !!

I hope you all dont mind if I reply to an old thread -- i just wanted to bring it to everyones attention that its retarded to used any other 5-HT2a antagonizing anti-histamine except for cyproheptadine

its the ONLY ONE that leaves alone dopamine and has low affinity for the "Good" 5-HT-1a receptor -- its binding profile charactoristics have some how passed up the medical and psychiatric community of the world, who instead gives seroquel, hydroxyzine, trazadone and others for the explicit purpose of antagonizing 5-HT2a, when right in front of their noses there exists something far-more selective for 5HT2a and a few other 5-HT subtypes, yet LOW AFFINITY FOR 5-ht-1a and Dopamine !!!

This is so important i logged in and posted, and i never bother posting anywhere except lunatic outpost sometimes.

PLEASE make psychiatrists aware that its retarded to target 5-HT-2a with dirty unselective drugs when CYPRO exists !!!!

Its a long-time custom now for psychiatrists to use 5-HT-2a Antagonists off-label for disorders other than schizo-spectrum; and yet the psychiatric science community has not noticed that Cyproheptadine would be most-ideal for this purpose !! LOOK at this Profile and compare it to all the other drugs they use to antagonize 5-HT2a!! remember, its "Bad" to antagonize 5-HT1a and Dopamine when you are only looking to target 2a.... LOOK -- its 59 nm for 1a, yet 2.2 and less for other 5-HT's and over 100 for D1 and D2 !!

Not that Cyproheptadine can be catagorized as a "Great Help" to anyone, but still, This Image and a print out of this forum post should be on the desk of every psychiatrist on Earth

Try to find me just ONE other drug that has such high affinity for the Excitotory 5-HT subtypes yet much lower affinity for the inhibitory 5-HT-1a and the important D1 and D2 receptors......WHy the hell are psychiatrists giving everyone seroquel, trazadone, hydroxyzine and such when Cypro can be tried first to see if it works, then resort to those others secondly!?!?!

because seroquel has been marketed heavily by big pharma because its cheap to produce.

 

[Ligaturd]

Yep. Off label usage and prescribing of an old medication to squeeze some more money out of it. I hear about people being put on Seroquel for anxiety and sleep problems. It's quite common now. My grandmother was on her deathbed, they had her in the hospital for a few months by then. They were draining blood out of her internal organs and they punctured her stomache. They couldn't do surgery. They gave her Haldol to put her out instead of just the usual Ativan and Fentanyl that they use for palliative care and she became incommunicable, restless, unable to talk or eat, kept trying to get up and pull her gown off. These are all symptoms of tardive akasthisia and parkinsonianism. When I came in they put her on Ativan and blamed her symptoms on her liver shutting down and her having Parkinsons which no one had mentioned before but as soon as I heard Haldol I called them on it, and they quickly recanted their story. Neuroleptics are being given despite the risks just to satisfy the stigma of giving people narcotics. This woman was on her death bed and their first reaction was to give her Haldol and avoid "drugs of abuse". That is the logic behind the Seroquel although Seroquel acts mostly as an anti-cholinergic under 100mgs. I just don't think it's right and there has been a definite increase in the usage of neuroleptics these past years.

 

[Tone303]

Yep. Off label usage and prescribing of an old medication to squeeze some more money out of it. I hear about people being put on Seroquel for anxiety and sleep problems. It's quite common now. My grandmother was on her deathbed, they had her in the hospital for a few months by then. They were draining blood out of her internal organs and they punctured her stomache. They couldn't do surgery. They gave her Haldol to put her out instead of just the usual Ativan and Fentanyl that they use for palliative care and she became incommunicable, restless, unable to talk or eat, kept trying to get up and pull her gown off. These are all symptoms of tardive akasthisia and parkinsonianism. When I came in they put her on Ativan and blamed her symptoms on her liver shutting down and her having Parkinsons which no one had mentioned before but as soon as I heard Haldol I called them on it, and they quickly recanted their story. Neuroleptics are being given despite the risks just to satisfy the stigma of giving people narcotics. This woman was on her death bed and their first reaction was to give her Haldol and avoid "drugs of abuse". That is the logic behind the Seroquel although Seroquel acts mostly as an anti-cholinergic under 100mgs. I just don't think it's right and there has been a definite increase in the usage of neuroleptics these past years.

Thats of the utmost Dark & Evil Torture. From what i read, most doctors & nurses have very low intelligence and are metaphorically like dumb blank weak-minded animals. Very dull with nearly no intellectual sharpness at all, dont really know anything except the brand of drug and its indications. Sadly, those in positions arent qualified to hold the positions they hold, but this doesnt mean the positions are going to disappear, of course not.

And pretend for a moment im telling you the absolutely truth, if people arent qualified to hold the positions they hold, and they were told this, would they (A) reply "darn that is so profound & sad" or would they (B) go into psychological denial and claim they are qualified? what would nurses, doctors, legislators, judges, executives and others say? which one if it were true? A or B?

Depending on the person, a neuroleptic can be an intense torture that is worse than being branded with a hot iron, but the person administering the neuroleptic would claim in 100% of people 100% of the time, neuroleptics are not worse than being branded with a hot iron. They would go into Psychological Denial unless they were adminstered one themselves and got a feeling between their shoulder blades then had akathisia, because they are dumb savage animals hardly enough intelligence to be a doctor or nurse, and quite degenerate of mind. A monkey has no idea how stupid it is compared to a human. Neither would a doctor know how dumb it is compared to a person with the knowledge the doctor doesnt have, just like the monkey. In fact, the dull-minded sociopath's only defense to this post is that it would make-up a false descriptive generalization about this post or cite its credentials, or both..

Any and Every time one would: 1) tell them how stupid they are and why or 2) challenge them off-duty to take a neuroleptic not sourced from their hospital, they 1) go into denial and play dumb like its make-believe they are stupid instead of actually stupid and/or 2) decline the challenge, respectively