Hydroxyzine and Psychedelics: Mixed interaction at 5HT-2a

[Saucy]

For my general anxiolytic, I recently switched to Hydroxyzine (from Gabapentin, which, had the worst withdrawals I have ever experienced despite considerable tapering even after only 8 months of use; easily worse than cold turkey on Clonazepam after 18 months of daily use). I find hydroxyzine's mechanism of action for this function (as an inverse agonist on the 5-HT2a receptor) to be particularly interesting, primarily because it acts on the same receptor that produces psychedelic effects (albeit in the opposite "direction").

As a regular user of psychedelics (i.e. 2-3 times per month), I am curious how daily use of hydroxyzine would affect the psychedelic experience, as well as what concurrent administration of a 5-HT2a agonist and a 5-HT2a inverse agonist will produce. Is it possible that regular use of hydroxyzine could upregulate my response to psychedelics?

Would administration of hydroxyzine while on a psychedelic cancel some or all of its effects? If so why are 5-HT2a inverse agonists or antagonists not used to counteract the effects of psychedelics, in the case of, say, a bad trip? It is known that tolerance to hydroxyzine's anxiolytic effects builds with continued use (albeit slowly), and tends to fall quickly. With this fact in mind, would use of a 5-HT2a agonist while tolerant to the anxiolytic effects of a 5-HT2a inverse agonist be more likely to produce anxiety?

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Side Topic:

It is known that 2nd position Aryl-subnstututued tryptamines act as selective high-affinity antagonists for the h5-HT2A receptor. Why has no pharmaceutical company pursued development of such a drug as a non-addictive anxiolytic?

 

[chaos_destroy]

I would imagine hydroxyzine would inhibit any psychedelics function. Many atypical anti-psychotics are 5-ht2A receptor antagonists and are indeed very useful in aborting a bad trip. As for upregulation the 5-ht2 receptors are different to other receptors in that both antagonist and agonists cause down regulation which means hydroxyzine could cause a tolerance to psychedelics even if you took a break for a few days from the hydroxyzine.

 

[Saucy]

How would an agonist and an inverse agonist both cause downregulation? Do you have any more information on why that is?

 

[chaos_destroy]

The review paper below talks about it. It apparently involves internalization and degradation rather than transcriptional down regulation. The cholecystokinin (CCK) receptor, human vasopressin V2, and A1 adenosine receptor have also been shown to be down regulated by antagonists.

Gray, J. A. and B. L. Roth (2001). "Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists." Brain Res Bull 56(5): 441-451.

 

[atara]

5-ht2a antagonists tend to downregulate 5-ht2a receptors. I have heard that inverse agonists may promote upregulation, but I can't recall where and I may be mistaken. However, methamphetamine does upregulate 5-ht2a and 5-ht2c:

http://www.ncbi.nlm.nih.gov/pubmed/17957734

but it is not advisable to use this to increase the psychedelic response.

 

[Saucy]

Thanks for the information. I am looking into this matter further and will update when I have additional info.

 

[Saucy]

A comprehensive review of the following literature has shown that atara is fortunately correct about inverse-agonists promoting upregulation at 5-HT2a. So... would it be unreasonable to say that regular administration of Hydroxyzine would actually lower one's tolerance to serotonergic psychedelics?

Edit: Lol at the unintentional emoticons.

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Leurs, R., Smit, M. J., Alewijnse, A. E., & Timmerman, H. (1998). Agonist-independent regulation of constitutively active G-protein-coupled receptors. Trends Biochem Sci 23(11), 418−422.

Milligan, G., & Bond, R. A. (1997). Inverse agonism and the regulation of receptor number. Trends Pharmacol Sci 18(12), 468−474.

Strange, P. G. (2002). Mechanisms of inverse agonism at G-protein-coupled receptors. Trends Pharmacol Sci 23(2), 89−95.

Aloyo, V. J., Dave, K. D., Rahman, T., & Harvey, J. A. (2001). Selective and divergent regulation of cortical 5-HT2A receptors in rabbit. J Pharmacol Exp Ther 299(3), 1066−1072.

Dave,K.D.,Harvey, J.A.,& Aloyo, V. J. (2007). The time–course for up- and down-regulation of the cortical 5-hydroxytryptamine (5-HT)2A receptor density predicts 5-HT2A receptor-mediated behavior in the rabbit. J Pharmacol Exp Ther 323(1), 327−335.

 

[N0 W4RN1NG]

Hmm, does anyone know if the related antihistamine orphenadrine is also a 5HT-2A inverse agonist?

Because that shit has some serious anxiolysis\relaxation for a fucking H1 antagonist...

Also, quick side note, I am prescribed 100mg trazodone, a 5HT2A antagonist among other things...

It is a terrible drug to use to 'abort' a trip.

Trazodone increases body high and visuals from LSD.

Then again, it [trazodone] is really a dirty drug...one cannot assume the psychedelic potentiation is a direct result of 5HT-2A blockade...

 

[chaos_destroy]

Is hydroxyzine an antagonist or an inverse agonist? Wiki says its an antagonist but the paper they reference is old (1990). I haven't been able to find anything new claiming otherwise.

 

[Blowmonkey]

Me neither.

Hmm, does anyone know if the related antihistamine orphenadrine is also a 5HT-2A inverse agonist?

mACh receptor antagonist (anticholinergic)
H1 receptor antagonist (antihistamine)
NMDA receptor antagonist
NET blocker (norepinephrine reuptake inhibitor)
Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker
HERG potassium channel blocker

http://en.wikipedia.org/wiki/Orphenadrine

 

[Saucy]

Is hydroxyzine an antagonist or an inverse agonist? Wiki says its an antagonist but the paper they reference is old (1990). I haven't been able to find anything new claiming otherwise.

+1

I would really like this answered definitively. I was sure that it was an inverse agonist, but when I went to double check my source after reading this post, I could not find it. I did however find two studies that reference it as an antagonist at the 5-HT2a receptor

 

[dhar174]

Hydroxyzine is a H1 inverse agonist, so someone may have confused that with its 5hta activity. I couldnt find any reference to it being a 5ht2a inverse agonist either.

 

[N0 W4RN1NG]

Hydroxyzine is a 5HT2A antagonist.

 

[Saucy]

^Yeah I looked into the matter further, and this is definitely correct.

 

[MichelJacques]

Sorry to dig up such an old thread, but made more sense for my question than starting a new one. Does anybody have a citation from the primary lit that hydroxyzine is an antagonist of the 5HT2a receptor? I can't find any clinical or experimental data supporting this pharmacology.

 

[blueberries]

I use Hydroxyzine for a quick and easy trip killer if I get bored. I wouldn't suggest using it together as you'll experience absolutely no visuals, but if you're going for this then try some Iprocin, wonderful substance IMO.