Antihistamines as P450 2D6 inhibititors (increase opiates effect)

[Ethyl]

Swie has been using hydroxyzine with his heroin/opium doses, and he has found that not only it has a more dreamlike sedation to the effect but at the same time it extends the high for a couple more hours.
Then swie took it with codeine, and noticed a decreased effect, he then google about hydroxyzine and p4 2d6 and he came with this info:

Classic antihistamines, namely diphenhydramine, chlorpheniramine, clemastine, perphenazine, hydroxyzine, and tripelennamine, share structural features with substrates and inhibitors of the polymorphic cytochrome P450 (CYP) isozyme CYP2D6. Therefore, the current study was undertaken to characterize the in vitro inhibition of CYP2D6 by these commonly used, histamine H1 receptor antagonists. Microsomal incubations were performed using bufuralol as a specific CYP2D6 substrate and microsomes derived from human cells transfected with CYP2D6 cDNA. Reaction velocities were assessed in the absence and presence of antihistamines (20 microM) at 11 substrate concentrations (1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, and 100 microM), as well as at three nonsaturating substrate concentrations (2.5, 5, and 20 microM) and three inhibitor concentrations (5, 20, and 50 microM). In the presence of all antihistamines, the Vmax and KM of bufuralol 1'-hydroxylation were significantly altered, compared with the uninhibited reaction (p < 0.05). Lineweaver-Burke plots suggested competitive inhibition of the reaction by diphenhydramine and mixed inhibition by all other antihistamines tested. Diphenhydramine and chlorpheniramine, with estimated Ki values of approximately 11 microM, were the weakest inhibitors of CYP2D6 in vitro. Whereas tripelennamine, promethazine, and hydroxyzine were similar in their inhibitory capacities (Ki approximately 4-6 microM), clemastine appeared to be significantly more potent, with a Ki of approximately 2 microM. These data demonstrate that classic histamine H1 receptor antagonists, available in over-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the range of their expected hepatic blood concentrations, suggesting that, under specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.

Source: hxxp://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=9616188&do pt=Citation

So appears that classic antihistamines are in fact good CYP2D6 inhibitors, and by that way they prolong the effect from opiates that are metabolised by CYP2D6.
And they add analgesia/sedation/increased opiates effects too. They are prescribed as a way to increase analgesia/effects from opiates.

[Bajeda]

Concerning hydroxyzine....

Originally Posted by Erowid Tidbit

Another practice reportedly employed by some narcotic users is combining hydroxyzine with opiates to potentiate their effects. This is said to produce a rough doubling of intensity with the addition of unwanted side effects like a dry mouth. [Anonymous 2000] It appears to have no effect on the development of tolerance.

Originally Posted by Other Forum

Hydroxyzine is one of the best sedative antihistamine. It is one of the strongest Opiate/Opioid potentiator. Take 50 or 75mg orally before taking your Opiate/Opioid, or take 50mg IV with your Opiate/Opioid......

[Referring to sedative and anti-cholinergic antihistamines] Antihistamines make Morphine stronger, they make you nod harder. They also cure many side-effects, such as the itching, the nausea...

If you want to potentiate your Opiates, take 50mg Atarax (Hydroxyzine) orally.

Quite a few people seemed to agree on 50mg of Hydroxyzine as a good dose for potentiation.


A certain panda has a good amount of hydroxyzine plus a diminished stash of opiates, so he may attempt an experiment on opiate potentiation with hydroxyzine, though probably at a low dose.

Does anyone out there have experience using hydroxyzine as an opiate potentiator? If so, please describe any experiences so the panda has a better idea of what to expect and so he can better approximate dose and timing of ingestion.

[Bajeda]

Hydroxyzine mixed very nicely with the panda's hydrocodone, producing a much stronger experience than expected for the dose taken and a more relaxed one too it felt. The panda believes this combination is very desirable for future research, and while he wouldn't get into a habit of it (he doesn't have an opiate habit anyways) he feels he could save money by using hydroxyzine to potentiate certain opiates.

[Ethyl]

Swie was taking hydroxyzine with heroin daily and he noticed a loss of effect from the hydroxyzine boost, as swiy say but hydroxyzine is the best antihistamine for sedation/opiate potentiator.

[eltimmy]

Yea. Hence the promethazine in Houston's purple stuff. And the reports of the incredibly dangerous/stupid addition of atropine or scopolamine to heroin mixes occasionally popping up on the newswire.

[Bajeda]

A certain panda experimented with hydroxyzine as an opiate potentiator again, and found it to be just as effective as before with doses ranging from 30-50mg mixed with hydrocodone.

He is wondering though, if it is better to take the hydroxyzine 45min to 1hr before taking the opiates (as suggested by a member in another thread), or to take it around the same time as taking the opiates...

Anyone with experience using hydroxyzine as an opiate potentiator able to offer advice (or reasoning to back it up) regarding this query?

[OhCasey]

Swim has done hydroxyzine both an hour before and at the same time of and he thinks hydroxyzine works a lil better if used at or just moments before opiate dosing. Just his personal experience though.

[ChiselD]

SWIM has tried using Hydroxizine as an opiate potentiator to great astonishment. This works great using it maybe 20-30 minutes beforehand. I'm sure taking 25mgs an hour before, another 25 at 5-15 minutes before. Will get back to you on IV use, as my test bunny is in town and he'll be dancing with the Lady D tonight.

Sorry to bump this old thread but thought this would be of interest with anyone able to get Hydroxizine.

[ThinkinBig]

SWIM noticed a slight increase of effects taking this with his hydrocodone, but bc SWIM has such a tolerance it is hard to trule gauge. SWIM will be trying 50mg of hydroxyzine in conjunction with the big H later on today. SWIM is a user, but only through his nasal passageways and never the IV route. (Its been a few years and SWIM is perfectly content keeping things at this level)