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{{SummarySheet}}
{{SummarySheet}}
{{SubstanceBox/Hydroxyzine}}
{{SubstanceBox/Hydroxyzine}}
'''Hydroxyzine''' (also known as '''''alpha''-methylphenethylamine''', '''amfetamine''', and '''speed''') is a [[psychoactive class::stimulant]] substance of the [[chemical class::phenethylamine]] class.
Chemically, it is the parent compound of the [[substituted amphetamines]], a group which includes a diverse range of substances like [[bupropion]], [[phenmetrazine]], [[MDMA]], and [[DOx]]. Amphetamine acts by promoting the release of the [[neurotransmitters]] [[dopamine]] and [[norepinephrine]] in the brain,<ref>Kish, S. J. (2008). Pharmacologic mechanisms of crystal meth. ''Canadian Medical Association Journal'', ''178''(13), 1679-1682.</ref> and to a lesser extent serotonin.<ref>https://www.ncbi.nlm.nih.gov/pubmed/23757186</ref>


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'''Hydroxyzine''' is a first-generation [[psychoactive class::antihistamine]] substance of the diphenylmethylpiperazine/ethano-piperidine class.<ref>"Hydroxyzine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 21 Nov 2018.</ref> It acts primarily as a potent and selective histamine H<sub>1</sub> receptor antagonist,<ref>Szepietowski J, Weisshaar E (2016). Itin P, Jemec GB (eds.). Itch - Management in Clinical Practice. Current Problems in Dermatology. 50. Karger Medical and Scientific Publishers. pp. 1–80. ISBN 9783318058895.</ref><ref>Hosák L, Hrdlička M, et al. (2017). Psychiatry and Pedopsychiatry. Charles University in Prague, Karolinum Press. p. 364. ISBN 9788024633787.</ref> with anxiolytic effects likely attributable to weak antiserotonergic effects.<ref>Snowman AM, Snyder SH (December 1990). "Cetirizine: actions on neurotransmitter receptors". The Journal of Allergy and Clinical Immunology. 86 (6 Pt 2): 1025–1028. doi:10.1016/S0091-6749(05)80248-9. PMID 1979798.</ref>
 
Hydroxyzine is often used in the treatment of [[itchiness]], [[anxiety]], [[insomnia]], and [[nausea]] from motion sickness.<ref>"Hydroxyzine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 21 Nov 2018.</ref> Unlike many other first-generation antihistamines, hydroxyzine has low affinity for muscarinic acetylcholine receptors, and thus does not produce strong anticholinergic side effects responsible for the deliriant properties of drugs such as [[diphenhydramine]].<ref>Kubo N, Shirakawa O, Kuno T, Tanaka C (March 1987). "Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay". Japanese Journal of Pharmacology. 43 (3): 277–282. doi:10.1254/jjp.43.277. PMID 2884340.</ref>
 
Hydroxyzine sees little recreational use, limited mostly to where stronger anxiolytics, such as [[benzodiazepines]] or [[alcohol]], are not available.{{citation needed}} Unlike more commonly abused [[depressants]], it does not impact the [[neurotransmitter]] [[GABA]], instead acting via potent inverse agonism of the histamine H<sub>1</sub> receptor, which is responsible for its antihistamine and sedative effects.<ref>Szepietowski J, Weisshaar E (2016). Itin P, Jemec GB (eds.). Itch - Management in Clinical Practice. Current Problems in Dermatology. 50. Karger Medical and Scientific Publishers. pp. 1–80. ISBN 9783318058895.</ref><ref>Hosák L, Hrdlička M, et al. (2017). Psychiatry and Pedopsychiatry. Charles University in Prague, Karolinum Press. p. 364. ISBN 9788024633787.</ref> In addition to its antihistamine activity, it has been shown to act as a weak antagonist towards the serotonin 5-HT<sub>2A</sub> receptor, the dopamine D<sub>2</sub> receptor, and the α<sub>1</sub>-adrenergic receptor. It is prescribed for the treatment of [[generalized anxiety disorder]], short-term treatment of [[insomnia]], and allergic reactions .<ref>Rosario B. Hidalgo, David V. Sheehan, in Handbook of Clinical Neurology, 2012</ref> Like other antihistamines, high doses of hydroxyzine can prolong the QT interval, which may lead to the development of [[torsades de pointes]], a potentially fatal arrhythmia.<ref>British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. p. X. ISBN 978-0857112989.</ref> Combining hydroxyzine with other depressants such as benzodiazepines or alcohol can cause extreme symptoms such as dizziness or drowsiness, and as such it is recommended to use [[harm reduction practices]] if using this substance.


For tips on how to properly format a substance article, please refer to this document: [[Content Style Guide - Substance]]
Tolerance to the CNS effects of hydroxyzine develops rapidly, often in as few as 3-7 days.<ref> Levander S, Ståhle-Bäckdahl M, Hägermark O (1 September 1991). "Peripheral antihistamine and central sedative effects of single and continuous oral doses of cetirizine and hydroxyzine". European Journal of Clinical Pharmacology. 41 (5): 435–439. doi:10.1007/BF00626365. PMID 1684750. S2CID 25249362.</ref> Tolerance to its sedative effects builds faster than tolerance to its anxiolytic effects. Such, it is indicated for use in short-term or as-needed [[insomnia]] treatment.


==History and culture==
==History and Culture==
{{historyStub}}
{{historyStub}}
Hydroxyzine was first synthesized by Union Chimique Belge in 1956 and was approved for sale by Pfizer in the United States later that year.<ref>"Hydroxyzine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 21 Nov 2018.</ref><ref>Shorter E (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 9780195368741.</ref> Originally mostly given for nausea and allergies, it later began to be used in medicine for its anxiolytic properties. It is sometimes given as a substitute to benzodiazepines in surgeries to decrease anxiety and act as an anesthetic.  In the United Kingdom 28 doses cost less than a pound.<ref>British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. p. X. ISBN 978-0857112989.</ref> In the United States the wholesale cost in 2018 was about 0.05 USD per dose.<ref>"NADAC as of 2018-11-21". Centers for Medicare and Medicaid Services. Retrieved 21 Nov 2018.</ref> In the United States about 8 million prescriptions were written for hydroxyzine in 2016.<ref>British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. p. X. ISBN 978-0857112989.</ref>


==Chemistry==
==Chemistry==
{{chemistry}}
{{chemistry}}
Hydroxyzine is a member of the diphenylmethylpiperazine and ethano-piperidine class of drugs. Analogues of hydroxyzine include buclizine, cetirizine, cinnarizine, cyclizine, etodroxizine, meclizine, and pipoxizine among others. It is synthesized by the alkylation of 1-(4-chlorobenzhydryl)piperazine with 2-(2-Chloroethoxy)ethanopiperidine<ref>H. Morren, U.S. Patent 2,899,436 (1959); H. Morren, DE 1049383 (1954); H. Morren, DE 1061786 (1954); H. Morren, DE 1068262 (1954); H. Morren, DE 1072624 (1954); H. Morren, DE 1075116 (1954).</ref>
Hydroxyzine's chemical structure features a diphenylmethylpiperazine core, consisting of a piperazine ring bonded to a diphenylmethyl group. This structure is integral to its pharmacological effects, including its antihistaminic and anxiolytic properties.
==Pharmacology==
==Pharmacology==
{{pharmacology}}
{{pharmacology}}
Hydroxyzine acts primarily as a potent [[histamine]] H<sub>1</sub> receptor [[antagonist]].<ref>Szepietowski J, Weisshaar E (2016). Itin P, Jemec GB (eds.). Itch - Management in Clinical Practice. Current Problems in Dermatology. 50. Karger Medical and Scientific Publishers. pp. 1–80. ISBN 9783318058895.</ref><ref>Hosák L, Hrdlička M, et al. (2017). Psychiatry and Pedopsychiatry. Charles University in Prague, Karolinum Press. p. 364. ISBN 9788024633787.</ref> Hydroxyzine is notable for having lower affinity for muscarinic acetylcholine receptor relative to other first-generation antihistamines, like [[diphenhydramine]] - subsequently, hydroxyzine is less liable to cause hallucinatory states or delirium. In addition to antihistamine activity, hydroxyzine acts as an antagonist towards [[5-HT<sub>2A</sub>]] receptors (likely responsible for its [[anxiolytic]] effects), dopamine D<sub>2</sub> receptors, and α<sub>1</sub>-adrenergic receptors. Hydroxyzine is unique among first-generation antihistamines with regards to its anxiolytic properties.
In terms of its pharmacokinetics, hydroxyzine is metabolized rapidly and crosses the blood-brain barrier with ease. When taken orally, it is rapidly absorbed through the gastrointestinal tract and is metabolized in the liver. Effects typically begin within 15-30 minutes, with peak plasma concentrations occurring approximately two hours post-administration. Hydroxyzine and its metabolites have relatively long half-lives; however, the sedative effects generally last around 4-6 hours. In adults, the elimination half-life of hydroxyzine is approximately 20 hours.<ref>Jensen, C., & Mehta, N. (2016). Pharmacokinetics and Pharmacodynamics of Hydroxyzine. Journal of Pain and Symptom Management, 51(5), 872-877.</ref>
Low doses of hydroxyzine (where less than 20% of H<sub>1</sub> receptors are bound) are not associated with [[somnolence]], but high doses (where 50% or more of H<sub>1</sub> receptors are bound) cause [[sedation]].<ref name="pmid16890992">{{cite journal | vauthors = Yanai K, Tashiro M | title = The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies | journal = Pharmacology & Therapeutics | volume = 113 | issue = 1 | pages = 1–15 | date = January 2007 | pmid = 16890992 | doi = 10.1016/j.pharmthera.2006.06.008 }}</ref>
Hydroxyzine also exhibits anticholinergic and sedative properties, which can be beneficial in treating conditions like anxiety and tension. The anticholinergic properties of hydroxyzine are due to its ability to block muscarinic acetylcholine receptors, which can help reduce muscle spasms and other symptoms related to excessive cholinergic activity. The sedative properties of hydroxyzine are primarily due to its antagonism of central H<sub>1</sub> receptors and, to a lesser extent, its antagonism of serotonin 5-HT<sub>2A</sub> receptors. These combined actions contribute to its efficacy in managing anxiety and promoting relaxation.<ref>Howland RH. (2015). Hydroxyzine for anxiety. Journal of Psychosocial Nursing and Mental Health Services, 53(10), 21-24.</ref>
Hydroxyzine is also used to manage nausea and vomiting, primarily through its antihistamine effects. The drug's action on H<sub>1</sub> receptors helps alleviate symptoms of motion sickness and other vestibular disorders that can cause nausea. Additionally, hydroxyzine's antagonistic effects on dopamine D<sub>2</sub> receptors in the chemoreceptor trigger zone (CTZ) contribute to its antiemetic properties.<ref>Gan, T. J. (2017). Mechanisms underlying postoperative nausea and vomiting and neurotransmitter receptor antagonist-based pharmacotherapy. CNS Drugs, 21(11), 813-833.</ref>
As an antihistamine, hydroxyzine is effective in treating allergic reactions such as urticaria (hives) and chronic pruritus (itching). By blocking H<sub>1</sub> receptors, hydroxyzine reduces the effects of histamine release, which includes vasodilation, increased vascular permeability, and sensory nerve stimulation that causes itching.<ref>Kaplan AP. (2013). Chronic urticaria: Pathogenesis and treatment. Journal of Allergy and Clinical Immunology, 131(3), 594-602.</ref>


==Subjective effects==
==Subjective effects==
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{{effects/base
{{effects/base


|{{effects/physical|
{{effects/physical|
If applicable, a brief paragraph summary of the substance's physical effects may be included here.
 
You may select physical effects to add below [[Subjective effect index#Physical effects|here]].


*'''[[Effect::Physical effect]]'''  
*'''[[Effect::Sedation]]'''
*'''[[Effect::Physical effect2]]'''
*'''[[Effect::Motor control loss]]'''
*'''[[Effect::Physical effect3]]'''
*'''[[Effect::Respiratory depression]]'''
*'''[[Effect::Perception of bodily heaviness]]'''
*'''[[Effect::Dizziness]]'''
*'''[[Effect::Abnormal heartbeat]]'''
*'''[[Effect::Increased heart rate]]'''
*'''[[Effect::Difficulty urinating]]'''
*'''[[Effect::Itchiness]]''' - Itchiness is suppressed in low doses but increased in high doses.
*'''[[Effect::Nausea suppression]]''' - Hydroxyzine is indicated for treatment of nausea.
*'''[[Effect::Dehydration]]'''
*'''[[Effect::Cough suppression]]'''
*'''[[Effect::Tactile hallucinations]]''' - This effect only occurs at dangerously high doses, such as intentional overdoses.


}}
}}
{{effects/visual|
{{effects/visual|
If applicable, a brief paragraph summary of the substance's visual effects may be included here.


You may select visual effects to add below [[Subjective effect index#Visual effects|here]].
*'''[[Effect::Visual acuity suppression]]''' - Like many [[depressants]], hydroxyzine is known to cause blurred or otherwise suppressed visual acuity in high doses. This is less likely to occur than other [[depressants]], however it can still present itself at higher doses, or if the user has a low tolerance.
 
*'''[[Effect::External hallucinations]]''' - This effect is nowhere near as pronounced as [[diphenhydramine]] and only occurs in extremely high doses or when combined with other CNS depressants, such as [[lithium]], [[valproate]], [[antipsychotics]], or [[ethanol]].<ref> Anderson PO, Knoben JE, Troutman WG (2002). Handbook of Clinical Drug Data. pp. 794-6. ISBN 9780071363624. PMC 1875767. PMID 20313924.</ref> These experiences are often reported by individuals with psychiatric comorbidities who are prescribed [[mood stabilizers]], [[antipsychotics]], or [[tricylic]]/[[tetracyclic]] [[antidepressants]].
====Enhancements====
*'''[[Effect::Visual acuity effect1]]'''
 
====Distortions====
*'''[[Effect::Visual distortion effect1]]'''
 
====[[Effect::Geometry]]====
If applicable, a brief paragraph summary describing the visual geometry produced by the substance may be included here.
====Hallucinatory states====
If applicable, a brief summary of the substance's visual effects profile may be written here.
 
*'''[[Effect::Hallucinatory states1]]'''


}}
}}
{{effects/paradoxical|


|{{effects/cognitive|
Paradoxical reactions to hydroxyzine occur mostly in high doses and can include nausea, itchiness, agitation, restlessness, and muscle spasms. Extremely high doses can result in seizures, vomiting, uncontrollable shaking, and other effects typical of an antihistamine overdose.
If applicable, a brief paragraph summary of the substance's cognitive effects may be included here.
 
You may select from a list of cognitive effects to add below [[Subjective effect index#Cognitive effects|here]].
 
*'''[[Effect::Cognitive effect1]]'''
*'''[[Effect::Cognitive effect2]]'''
*'''[[Effect::Cognitive effect3]]'''


}}
}}
{{effects/auditory|
{{effects/cognitive|
If applicable, a brief paragraph summary of the substance's auditory effects may be included here.


You may select from a list of auditory effects to add below [[Subjective effect index#Auditory effects|here]].
The general head space of hydroxyzine is described by many as one of mild to moderate sedation.


*'''[[Effect::Auditory effect1]]'''
The most prominent of these cognitive effects generally include:
*'''[[Effect::Auditory effect2]]'''
*'''[[Effect::Anxiety suppression]]''' - This effect is mild compared to [[benzodiazepines]].
*'''[[Effect::Disinhibition]]''' - This effect is mild compared to [[benzodiazepines]].
*'''[[Effect::Thought deceleration]]'''
*'''[[Effect::Analysis suppression]]'''
*'''[[Effect::Amnesia]]''' - This only occurs in very high doses and is less pronounced than other [[depressants]].
*'''[[Effect::Emotion suppression]]''' - Antagonizing dopamine, adrenaline, and serotonin receptors, hydroxyzine exhibits similar emotional suppression to [[antipsychotics]], but far less pronounced.
*'''[[Effect::Language suppression]]''' - This only occurs in very high doses and may be indictive of an overdose.
*'''[[Effect::Confusion]]'''
*'''[[Effect::Creativity suppression]]'''  
*'''[[Effect::Decreased libido]]'''


}}
}}
{{effects/multisensory|
{{effects/aftereffects|
If applicable, a brief paragraph summary of the substance's multisensory effects may be included here.


You may select from a list of multisensory effects to add below [[Subjective effect index#Multisensory effects|here]].
*'''[[Effect::Anxiety|Rebound anxiety]]''' - Rebound anxiety is a commonly observed effect with [[anxiety suppression|anxiety relieving]] substances like hydroxyzine. It typically corresponds to the total duration spent under the substance's influence along with the total amount consumed in a given period, an effect which can easily lend itself to cycles of dependence and addiction. Because hydroxyzine is a weak anxiolytic compared to [[benzodiazepines]], addiction is extremely rare, but physical dependence is possible with frequent use.
 
*'''[[Effect::Sleepiness|Residual sleepiness]]''' - While hydroxyzine can be used as an effective [[hypnotic|sleep-inducing]] aid, its effects may persist into the morning afterward, which may lead users to feeling "groggy" or "dull" for up to a few hours.  
*'''[[Effect::Multisensory effect1]]'''  
*'''[[Effect::Thought deceleration]]'''  
*'''[[Effect::Multisensory effect2]]'''  
*'''[[Effect::Thought disorganization]]'''  


}}
}}
{{effects/transpersonal|
If applicable, a brief paragraph summary of the substance's transpersonal effects may be included here.


You may select from a list of transpersonal effects to add below [[Subjective effect index#Transpersonal effects|here]].
===Experience reports===
There are currently no anecdotal reports which describe the effects of this compound within our [[experience index]]. Additional experience reports can be found here:
* [https://www.erowid.org/experiences/subs/exp_Pharms_Hydroxyzine.shtml Erowid Experience Vaults: Hydroxyzine]


*'''[[Effect::Transpersonal effect1]]'''
==Toxicity, Harm Potential, and Dangerous Interactions==
*'''[[Effect::Transpersonal effect2]]'''
{{toxicity}}
It is strongly recommended that one use [[responsible use|harm reduction practices]] when using this substance. It can cause extreme drowsiness and lack of coordination, and can increase the sedating effects of alcohol and other CNS depressants.


}}
Hydroxyzine is contraindicated in patients with risk factors for QT prolongation, a cardiac electrical disturbance which causes the heart muscles longer than normal to recharge between beats. Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP), which can be fatal. Caution is recommended during the concomitant use of drugs known to prolong the QT interval, which include quinidine, antiarrhythmics, certain antipsychotics (e.g., ziprasidone, iloperidone, clozapine, quetiapine, chlorpromazine), certain antidepressants (e.g., citalopram, fluoxetine), certain antibiotics (e.g., azithromycin, erythromycin, clarithromycin, gatifloxacin, moxifloxacin); and others (e.g., pentamidine, methadone, ondansetron, droperidol).<ref>Vistaril® (hydroxyzine pamoate) [package insert]. New York, New York: Pfizer Labs; 2016.</ref>
}}
===Experience reports===
There are currently {{#ask:[[Category:SUBSTANCE]][[Category:Experience]] | format=count}} experience reports which describe the effects of this substance in our [[experience index]].
{{#ask: [[Category:SUBSTANCE]][[Category:Experience]]|format=ul|Columns=1}}
Additional experience reports can be found here:
* [https://www.erowid.org/experiences/subs/exp_SUBSTANCE.shtml Erowid Experience Vaults: SUBSTANCE] <!-- Check the link to see if it exists -->


==Toxicity and harm potential==
{{toxicity}}
It is strongly recommended that one use [[responsible use|harm reduction practices]] when using this substance.
===Lethal dosage===
===Tolerance and addiction potential===
===Tolerance and addiction potential===
===Dangerous interactions===
 
{{DangerousInteractions}}
As discussed, hydroxyzine interacts with a variety of receptors and can cause a variety of effects. At very high doses, it may cause delirium, similar to other antihistamines like diphenhydramine. Its sedating, anxiolytic effects can be habit forming and result in psychological addiction, tolerance, and dependence. Tolerance to Hydroxyzine can develop fast and psychological addiction can be common in patients treated for anxiety and insomnia with hydroxizine.{{citation needed}}
{{DangerousInteractions/Intro}}


==Legal status==
==Legal status==
{{LegalStub}}
*'''Austria''': Hydroxyzine is available by prescription only.
*'''Brazil''': Hydroxyzine can be bought without a prescription, over the counter. <ref>Anvisa. (2016). PARECER GESEF/GGMED/DIRE2/ANVISA. https://www.gov.br/anvisa/pt-br/setorregulado/regularizacao/medicamentos/medicamentos-isentos-de-prescricao/arquivos/parecer-hidroxizina.pdf</ref>
*'''United States''': Hydroxyzine is available by prescription only.
*'''United Kingdom''': Hydroxyzine is available by prescription only.
*'''Russia''': Hydroxyzine is available by prescription only.
*'''Turkey''': Hydroxyzine can be bought without a prescription, over the counter.


==See also==
==See also==
*[[Responsible use]]
*[[Responsible use]]
*[[Antihistamine]]
*[[Acetylcholine]]
*[[GABA]]
*[[Sedative]]
*[[Dissociative]]
*[[Deliriant]]


==External links==
==External links==
(List along order below)
*[https://en.wikipedia.org/wiki/Hydroxyzine Hydroxyzine (Wikipedia)]
* [https://en.wikipedia.org/wiki/SUBSTANCE SUBSTANCE (Wikipedia)]
*[https://isomerdesign.com/PiHKAL/explore.php?id=9423 Hydroxyzine (Isomer Design)]
* SUBSTANCE (Erowid Vault)
* SUBSTANCE ([''PiHKAL'' or ''TiHKAL''] / Isomer Design)


==Literature==
==Literature==
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<references />
<references />


[[Category:Psychoactive substance]][[Category:Proofread]][[Category:Approval]]
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