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/SIGNS AND SYMPTOMS/ In general, overdosage of hydroxyzine may be expected to produce effects that are extensions of common adverse reactions; excessive sedation has been the principal effect reported. Hypotension, although rare, may also occur.[American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2630] **PEER REVIEWED**", (1).
Given this information, it seems likely that very high doses of hydroxyzine would be appropriate for insomnia. The primary side effect of hydroxyzine is one of therapeutic value: namely sedation.
At 400 mg per day, hydroxyzine has been found effective for anxiety, (2). Patient drop out rate due to side effects was high; given that sedation was the chief side effect, this is evidence for its effectiveness for insomnia. However, some subjects reported mild, as opposed to marked, sedation. Therefore, it's plausible that higher doses could be required by some people. Nevertheless, if 400 mg is administered in a single dose at night, then peak values and thus effectiveness should be greater than 400 mg throughout the day.
Tolerance to the sedating effects of antihistamines develops rapidly. Complete tolerance to sedation from diphenhydramine (benadryl) occurs on the fourth day of twice daily administration, (3). Three times daily administration results in complete tolerance on the third day, (4). However, antihistamines increase slow wave sleep (SWS, AKA deep sleep) in mice, rats, and guinea pigs, (5,6). Expectedly, this enhanced sleep results in rebound wakefulness upon withdrawal, (6). Therefore, it is not clear whether tolerance to antihistamine sedation per se develops rapidly, or if apparent tolerance is simply a sleep surplus. In any case, this insures that daytime sedation is unlikely after a few days of use for insomnia.
Regardless, hydroxyzine is also a 5-HT2A antagonist. In addition to improving sleep architecture, 5-HT2A antagonists are appealing because they lack tolerance, generally displaying reverse tolerance instead, (7,8). That is to say, one becomes more sensitive to the effects of the drug with repeated use, as contrasted to drugs losing their effectiveness in the case of normal drug tolerance.
Most antihistamines have anticholinergic side effects. While low acetylcholine is important during SWS, high levels are important for REM sleep, (9). For this reason, diphenhydramine reduces REM sleep, while less anticholinergic antihistamines (i.e. ketotifen) do not, (10). Hydroxyzine has comparatively insignificant anticholinergic effects, (11).
Hydroxyzine in doses up to 100 mg is able to improve sleep in PTSD, (12). However, 1 mg/kg (or about 70 mg for a normal adult) hydroxyzine to children is not as efficacious as 50 mg/kg chloral hydrate, (13). Nevertheless, melatonin plus 1.5 mg/kg hydroxyzine is able to reduce the need to take chloral hydrate from 37.1% to 6.7% in children undergoing EEG analysis, (14). Anecdotes had interested me in the 200-300 mg dose range. The study referenced above (2) makes me think that 400 mg may be adequate for most people, but not for everyone. I had been taking 150 mg hydroxyzine nightly for several weeks (Blog post) and have found it somewhat helpful, yet generally inadequate. I would like to try 300-400 mg.
References
(1) https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+68-88-2
(2) Rickels, K., Gordon, P. E., Zamostien, B. B., Case, W., Hutchison, J., & Chung, H. (1970). Hydroxyzine and chlordiazepoxide in anxious neurotic outpatients: A collaborative controlled study. Comprehensive psychiatry, 11(5), 457-474. Abstract, Sci-hub
(3) Richardson, G. S., Roehrs, T. A., Rosenthal, L., Koshorek, G., & Roth, T. (2002). Tolerance to daytime sedative effects of H1 antihistamines. Journal of clinical psychopharmacology, 22(5), 511-515.
(4) Schweitzer, P. K., Muehlbach, M. J., & Welsh, J. K. (1994). Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. Journal of allergy and clinical immunology, 94(4), 716-724.
(5) Lin, J. S., Sergeeva, O. A., & Haas, H. L. (2011). Histamine H3 receptors and sleep-wake regulation. Journal of Pharmacology and Experimental Therapeutics, 336(1), 17-23.
(6) Ikeda-Sagara, M., Ozaki, T., Shahid, M., Morioka, E., Wada, K., Honda, K., … Ikeda, M. (2012). Induction of prolonged, continuous slow-wave sleep by blocking cerebral H1 histamine receptors in rats. British Journal of Pharmacology, 165(1), 167–182. http://doi.org/10.1111/j.1476-5381.2011.01547.x
(7) Vanover, K. E., & Davis, R. E. (2010). Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nature and Science of Sleep, 2, 139–150.
(8) Yadav, P. N., Kroeze, W. K., Farrell, M. S., & Roth, B. L. (2011). Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo. The Journal of Pharmacology and Experimental Therapeutics, 339(1), 99–105.
(9) Gais, S., & Born, J. (2004). Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proceedings of the National Academy of Sciences, 101(7), 2140-2144.
(10) Katayose, Y., Aritake, S., Kitamura, S., Enomoto, M., Hida, A., Takahashi, K., & Mishima, K. (2012). Carryover effect on next‐day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial. Human Psychopharmacology: Clinical and Experimental, 27(4), 428-436. Sci-hub
(11) Kubo, N., SHIRAKAWA, O., KUNO, T., & TANAKA, C. (1987). Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay. The Japanese Journal of Pharmacology, 43(3), 277-282.
(12) Ahmadpanah, M., Sabzeiee, P., Hosseini, S. M., Torabian, S., Haghighi, M., Jahangard, L., ... & Brand, S. (2014). Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder. Neuropsychobiology, 69(4), 235-242.
(13) Sezer, T., & Alehan, F. (2013). Chloral hydrate versus hydroxyzine HCL for sedation prior to pediatric sleep EEG recording. International Journal of Neuroscience, 123(10), 719-723.
(14) Dirani, M., Nasreddine, W., Melhem, J., Arabi, M., & Beydoun, A. (2017). Efficacy of the sequential administration of melatonin, hydroxyzine, and chloral hydrate for recording sleep EEGs in children. Clinical EEG and neuroscience, 48(1), 41-47.
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