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4-Hydroxyamphetamine
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Hydroxyamphetamine
INN: Hydroxyamfetamine
Clinical data
Trade namesParedrine, Paremyd, Pedrolon, Mycadrine, Paredrinex, others
Other names4-Hydroxyamphetamine; 4-HA; Hydroxyamfetamine; Oxamphetamine; Norpholedrine; para-Hydroxyamphetamine; PHA; α-Methyltyramine; Methyltyramine, Hydroxyamphetamine (USAN US)
Routes of
administration		Eye drops
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 4-(2-aminopropyl)phenol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.002.866 Edit this at Wikidata
Chemical and physical data
FormulaC9H13NO
Molar mass151.209 g·mol−1
3D model (JSmol)
  • NC(C)Cc1ccc(O)cc1
  • InChI=1S/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3 checkY
  • Key:GIKNHHRFLCDOEU-UHFFFAOYSA-N checkY
  (verify)

Hydroxyamphetamine, also known as 4-hydroxyamphetamine or norpholedrine and sold under the brand names Paredrine and Paremyd among others, is a sympathomimetic medication used in eye drops to dilate the pupil for eye examinations.[1][2][3][4]

Hydroxyamfetamine acts as a norepinephrine releasing agent and hence is an indirectly acting sympathomimetic.[5][6] It is a substituted phenethylamine and amphetamine.[4]

Hydroxyamphetamine appeared to remain marketed only in the Czech Republic as of 2004.[3]

Medical uses

[edit]

Hydroxyamphetamine is used in eye drops to dilate the pupil (a process called mydriasis) so that the back of the eye can be examined. This is a diagnostic test for Horner's syndrome. Patients with Horner's syndrome exhibit anisocoria brought about by lesions on the nerves that connect to the nasociliary branch of the ophthalmic nerve.[7] Application of hydroxyamphetamine to the eye can indicate whether the lesion is preganglionic or postganglionic based on the pupil's response. If the pupil dilates, the lesion is preganglionic. If the pupil does not dilate, the lesion is postganglionic.[7]

Hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as an immediate follow up to another mydriatic drug (cocaine or apraclonidine), then the patient must wait anywhere from a day to a week before hydroxyamphetamine can be administered.[8][5] It also has the tendency to falsely localize lesions. False localization can arise in cases of acute onset; in cases where a postganglionic lesion is present, but the nerve still responds to residual norepinephrine; or in cases in which unrelated nerve damage masks the presence of a preganglionic lesion.[7][8]

Available forms

[edit]

Hydroxyamphetamine is a component of two controlled (prescription only), name-brand ophthalmic mydriatics: Paredrine and Paremyd. Paredrine consists of a 1% solution of hydroxyamphetamine hydrobromide[9]: 543  while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide.[10]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Hydroxyamphetamine acts as an indirect sympathomimetic and induces the release of norepinephrine which leads to mydriasis (pupil dilation).[5][6]

It has also been found to act as a serotonin releasing agent.[11] The drug produces the head-twitch response, a behavioral proxy of psychedelic effects, when it is given by intracerebroventricular injection in animals.[11] This effect is blocked by the serotonin receptor antagonists cyproheptadine and dimethothiazine, by the serotonin reuptake inhibitor fluoxetine, and by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA).[11] These findings suggest that hydroxyamphetamine-induced head twitches are due to activation of the serotonin 5-HT2A receptor and that they are mediated by induction of serotonin release as opposed to direct agonism of the serotonin 5-HT2A receptor.[11] Although hydroxyamphetamine produces the head-twitch response in animals, serotonin releasing agents are not necessarily hallucinogenic in humans, and hence their induction of head twitches in animals has been considered a false positive for psychedelic effects.[12][13][14]

It additionally decreases metabolism of serotonin and certain other monoamines by inhibiting the activity of monoamine oxidases (MAOs), particularly type A (MAO-A).[citation needed] The inhibition of MAO-A prevents metabolism of serotonin and catecholamines in the presynaptic terminal, and thus increases the amount of neurotransmitters available for release into the synaptic cleft.[11]

Like amphetamine, hydroxyamphetamine is an agonist of human TAAR1.[15]

Pharmacokinetics

[edit]

Hydroxyamphetamine is a major metabolite of amphetamine and a minor metabolite of methamphetamine. In humans, amphetamine is metabolized to hydroxyamphetamine by CYP2D6, which is a member of the cytochrome P450 superfamily and is found in the liver.[16][17] 4-Hydroxyamphetamine is then metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine or eliminated in the urine.[6]


Metabolic pathways of amphetamine in humans[sources 1]
Graphic of several routes of amphetamine metabolism
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
In humans, 4-hydroxyamphetamine is formed from CYP2D6 metabolism of amphetamine; 4-hydroxyamphetamine may subsequently be metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine.


Chemistry

[edit]

Hydroxyamphetamine, also known as 4-hydroxy-α-methylphenethylamine, 4-hydroxyamphetamine, or α-methyltyramine, is a substituted phenethylamine and amphetamine derivative. It is the 4-hydroxylated analogue of amphetamine, the N-demethylated analogue of pholedrine (4-hydroxy-N-methylamphetamine), and the α-methylated analogue of tyramine (4-hydroxyphenethylamine). Other analogues include α-methyldopamine, corbadrine (levonordefrin; α-methylnorepinephrine), and dioxifedrine (α-methylepinephrine).

It has a predicted log P of 0.58 to 1.4.[29][4][30]

Hydroxyamphetamine is used pharmaceutically as the hydrobromide salt.[1]

History

[edit]

Hydroxyamphetamine was first synthesized by 1910.[1]

In the 1990s, the trade name rights, patents, and new drug applications (NDAs) for Paredrine and Paremyd were exchanged among a few different manufacturers after a shortage of the raw material required for their production, which caused both drugs to be indefinitely removed from the market.[31] Around 1997, Akorn, Inc., obtained the rights to both Paredrine and Paremyd,[32] and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.[10][33][34]

In 2004, hydroxyamphetamine appeared to remain marketed only in the Czech Republic.[3]

Society and culture

[edit]

Names

[edit]

Hydroxyamphetamine is the generic name of the drug and its BANTooltip British Approved Name and DCFTooltip Dénomination Commune Française, while hydroxyamfetamine is its INNTooltip International Nonproprietary Name.[1][2][3] In the case of the hydrobromide salt, its generic name is hydroxyamphetamine hydrobromide and this is its USANTooltip United States Adopted Name.[1][2][3] It is also known by synonyms including methyltyramine, norpholedrine, and oxamphetamine.[1][2][3][29] The drug is sold under brand names including Paredrine, Paredrinex, Paremyd, Pedrolon, and Mycadrine.[1][3]

Other drugs

[edit]

4-Hydroxyamphetamine is also a metabolite of amphetamine and certain other amphetamines.[2]

Notes

[edit]

Reference notes

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

4-Hydroxyamphetamine

View on Grokipedia
from Grokipedia
4-Hydroxyamphetamine, also known as p-hydroxyamphetamine or hydroxyamfetamine, is a sympathomimetic amine that serves as an of and , characterized by a hydroxyl group substitution at the para position of the phenyl ring in the amphetamine structure, with the molecular formula C₉H₁₃NO. It functions primarily as a mydriatic agent in ophthalmic preparations, where it induces pupil dilation by releasing norepinephrine from adrenergic terminals, facilitating diagnostic eye examinations such as those for Horner syndrome. As an indirectly acting sympathomimetic, 4-hydroxyamphetamine stimulates the , particularly through at the trace amine-associated receptor 1 () and enhancement of norepinephrine release, which contributes to its mydriatic effects without significant systemic absorption when applied topically. In metabolism, it is formed via 2D6 ()-mediated of , representing approximately 3% of the parent compound's dose in humans, primarily in conjugated form, and is subsequently excreted in urine in a pH-dependent manner. Medically, it is formulated as (often combined with tropicamide under brand names like Paremyd) for safe, localized use in neuro-ophthalmic testing, with minimal side effects due to its slow onset and targeted action on Müller's muscle. Beyond its clinical applications, 4-hydroxyamphetamine has been studied for its role in the pharmacological profile of amphetamines, exhibiting lower toxicity compared to the parent compound while retaining central and peripheral sympathomimetic activity, though it is not approved for systemic use. Its stereoselective metabolism and detection in biological fluids also aid in forensic and toxicological analyses of amphetamine exposure.

Medical uses

Diagnostic applications

4-Hydroxyamphetamine serves as a mydriatic agent in topical ophthalmic formulations, primarily administered as 1% to induce dilation () for facilitating fundus examinations and other diagnostic ocular assessments. This application leverages its sympathomimetic properties to safely dilate the in patients, including those with shallow anterior chambers, due to its relatively slow onset and minimal side effects compared to other mydriatics. A key diagnostic role involves its use in the hydroxyamphetamine test, often following instillation, to localize s in the oculosympathetic pathway for Horner’s syndrome. In this protocol, one drop of 1% hydroxyamphetamine is instilled into both eyes 48 hours after cocaine testing, with responses evaluated after 45-60 minutes. Dilation of the affected indicates an intact postganglionic (third-order) , suggesting a preganglionic or central , whereas failure to dilate points to a postganglionic . Diagnostic limitations include the need for a 48-72 hour delay after or use to avoid interference from norepinephrine depletion, which can lead to false positives mimicking postganglionic lesions. In acute Horner’s syndrome within the first week post-injury, false-negative results may occur due to incomplete degeneration of presynaptic terminals. Additionally, normal variability in pupil response can limit localization accuracy, as a normal test does not reliably distinguish between central and preganglionic lesions, and transsynaptic degeneration may cause false positives in recent preganglionic cases. Drug availability further restricts widespread clinical use, particularly following the discontinuation of commercial formulations in recent years.

Available forms and administration

4-Hydroxyamphetamine, also known as hydroxyamphetamine, was previously available as a 1% hydroxyamphetamine hydrobromide ophthalmic solution under the brand name Paredrine for topical ocular administration to induce . However, Paredrine has been discontinued and is no longer commercially available. The combination product Paremyd, consisting of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide in a sterile ophthalmic solution packaged in 15 mL dropper bottles (NDC 17478-704-12), was introduced to enhance the speed and efficacy of for diagnostic purposes but was discontinued by the manufacturer in 2023 and is no longer available as of 2025. Due to these discontinuations, hydroxyamphetamine is no longer routinely used in clinical practice, with alternatives such as employed for and Horner syndrome evaluation. For the discontinued Paredrine, the standard dosing regimen involved instilling 1 drop of the 1% solution into the conjunctival sac of each eye, with an onset of typically occurring in 45-60 minutes and a duration extending up to 24 hours. For Paremyd, the recommended dose was 1-2 drops instilled into the conjunctival sac of the eye(s) requiring dilation, with onset within 15 minutes, maximum effect at 60 minutes, and recovery generally within 6-8 hours, though it may last up to 24 hours in some individuals. Administration of either formulation followed standard ophthalmic instillation procedures: the patient should tilt their head backward, pull down the lower to create a conjunctival pouch, and apply the drops without allowing the dropper tip to touch the eye or any surface to prevent . After instillation, the patient should close their eyes gently for 1-2 minutes, avoid or rubbing the eye, and apply light finger pressure to the inner corner of the eye () for at least 1 minute to reduce systemic absorption and nasolacrimal drainage. Soft contact lenses should be removed prior to administration due to potential and may be reinserted approximately after the drops are applied. Paremyd should be stored at controlled (15°C to 25°C or 59°F to 77°F) and protected from light to maintain stability. Historically, both Paredrine and Paremyd faced manufacturing and availability challenges in the late , leading to shortages; , Inc. acquired the rights from in 1997 and reintroduced Paremyd to the U.S. market in March 2002 following FDA approval. However, following 's in 2023, Paremyd was discontinued, resulting in its permanent withdrawal from the market.

Pharmacology

Pharmacodynamics

4-Hydroxyamphetamine functions primarily as a (NERA) by promoting the reversal of the (VMAT2), which displaces norepinephrine from synaptic vesicles into the cytoplasm, and by inhibiting the (NET), thereby preventing and increasing synaptic norepinephrine levels. This indirect sympathomimetic action leads to enhanced stimulation of alpha- and beta-adrenergic receptors without direct agonism at these sites. It also acts as a at trace amine-associated receptor 1 (), with an EC50 of approximately 0.05–0.2 μM in rat TAAR1-expressing cells, contributing to its overall sympathomimetic and effects by modulating monoamine signaling. Additionally, 4-hydroxyamphetamine exhibits serotonin releasing agent (SRA) properties, facilitating serotonin release, and weakly inhibits (MAO-A), reducing serotonin metabolism, though these effects are less pronounced compared to . The resulting physiological effects include elevated heart rate () and due to beta-adrenergic stimulation and alpha-adrenergic , respectively, as well as (pupil dilation) mediated by alpha-adrenergic activation in the iris. Relative to , 4-hydroxyamphetamine demonstrates reduced stimulation owing to its greater polarity and limited blood-brain barrier penetration, while retaining comparable peripheral sympathomimetic potency.

Pharmacokinetics

4-Hydroxyamphetamine is administered topically to the eye as a 1% solution (Paredrine), producing primarily local mydriatic effects with minimal systemic absorption due to its ophthalmic route of delivery. The onset of mydriasis occurs within 15-30 minutes, with peak dilation achieved at approximately 45-60 minutes and mydriasis lasting 3-6 hours; pupil size returns to normal within 24 hours. In cases of systemic absorption, 4-hydroxyamphetamine undergoes rapid distribution to peripheral tissues, including sympathetic nerve terminals. It is extensively metabolized in the liver, primarily via conjugation to form water-soluble metabolites, with further involvement of 2D enzymes in its hydroxylation and elimination pathways; inhibitors of CYP2D reduce urinary elimination of the compound. Excretion occurs mainly through the kidneys, with up to 3% of an administered dose (or equivalent from parent compounds) appearing as free 4-hydroxyamphetamine in urine and the majority as the conjugated form, totaling around 60-65% recovery in humans over 3-4 days; renal clearance is pH-dependent, accelerating in acidic urine. The elimination , inferred from studies of related amphetamines and its metabolic profile, ranges from 7 to 13 hours in adults, though specific data for standalone administration are limited. Pharmacokinetic variability is notable in certain populations. In the elderly, reduced hepatic metabolism and activity may prolong exposure, while hepatic impairment inhibits elimination, leading to higher plasma levels and extended effects. Renal dysfunction similarly delays clearance due to the urinary pathway. Drug interactions can alter kinetics: monoamine oxidase inhibitors potentiate sympathomimetic effects by preventing norepinephrine breakdown, risking enhanced toxicity, and inhibitors or substrates (e.g., certain antidepressants) may decrease 4-hydroxyamphetamine metabolism.

Metabolism and role as an amphetamine metabolite

4-Hydroxyamphetamine is formed as a primary of through aromatic primarily catalyzed by the in the liver. This pathway accounts for approximately 2% of 's overall metabolism in humans, though the exact fraction can vary based on individual activity. The process involves the addition of a hydroxyl group at the para position of the phenyl ring, yielding the pharmacologically active 4-hydroxyamphetamine. Following formation, 4-hydroxyamphetamine undergoes further metabolism, including oxidation by β-hydroxylase to produce 4-hydroxynorephedrine, a norepinephrine analog that retains sympathomimetic activity. It is also subject to phase II conjugation reactions, forming and conjugates that facilitate renal . These conjugated forms are primarily eliminated in , contributing to the detection of amphetamine use in screens where 4-hydroxyamphetamine serves as a . Genetic polymorphisms in significantly influence 4-hydroxyamphetamine production; poor metabolizers exhibit reduced levels of this metabolite due to diminished enzyme function, potentially altering 's overall disposition. In terms of pharmacological implications, 4-hydroxyamphetamine contributes to sympathomimetic effects of amphetamine, such as and increased . Toxicologically, 4-hydroxyamphetamine and its downstream metabolite 4-hydroxynorephedrine play roles in -induced , with 4-hydroxynorephedrine demonstrating greater in cells and longer persistence in the compared to the parent compound. This persistence underscores their potential contribution to long-term neuronal damage observed in amphetamine .

Chemistry

Chemical structure and properties

4-Hydroxyamphetamine has the molecular formula C₉H₁₃NO and the systematic IUPAC name 4-(2-aminopropyl)phenol. The has a molecular weight of 151.21 g/mol, while the salt, which is the form used clinically, has the formula C₉H₁₄BrNO and a molecular weight of 232.12 g/mol. It appears as a white to off-white crystalline solid. Key physical properties include a predicted logP value ranging from 0.58 to 1.0, indicating moderate ; a pKa of approximately 9.8 for the group and 10.5 for the phenolic hydroxyl; and in (predicted ~3 mg/mL) and (up to 30 mg/mL for the salt). These properties reflect its increased polarity due to the para-hydroxyl substitution on the phenyl ring compared to , which reduces its ability to penetrate the blood-brain barrier. For analytical identification, 4-hydroxyamphetamine exhibits characteristic spectroscopic features. In , the molecular ion appears at m/z 151, with prominent fragments at m/z 136 (loss of CH₃) and m/z 108. shows absorption bands at approximately 3300 cm⁻¹ (O-H and N-H stretch) and 1600-1500 cm⁻¹ (aromatic C=C stretch), while ¹H NMR reveals signals for the phenolic proton around 5-6 ppm, aromatic protons at 6.7-7.2 ppm, and the benzylic CH₂ at ~2.7 ppm.

Synthesis and preparation

4-Hydroxyamphetamine is typically synthesized in the laboratory through of 4-hydroxyphenylacetone (p-hydroxyphenyl-2-propanone) with , using a such as or catalytic . This method, which involves the formation of an intermediate followed by reduction to the , has been a standard approach since the early , with early descriptions appearing around via reduction of the precursor. Yields for this reaction can reach 70-90% under optimized conditions, such as in at 35°C and 1500 psi, which facilitates the process while minimizing side products. Alternative routes include the Henry reaction (nitroaldol condensation) of p-hydroxybenzaldehyde with to form a nitroalkene, followed by reduction to the ketone and subsequent . A protected variant starts from 4-methoxybenzaldehyde, condensing with in the presence of a primary catalyst to yield the nitropropene, which is reduced (e.g., with iron and HCl) to 4-methoxyphenylacetone, then aminated and demethylated. These multi-step processes allow access from commercially available aromatic aldehydes and are adaptable for analog synthesis. The hydrobromide salt, used in pharmaceutical formulations like ophthalmic solutions, is prepared by treating the with in a suitable , followed by and recrystallization to achieve purity greater than 99%. This salt formation enhances stability and for diagnostic applications. Synthesis challenges include achieving for the (S)-, which exhibits greater sympathomimetic activity; asymmetric using chiral catalysts or enzymes can yield enantiomeric excesses over 95%. Impurities such as 4-hydroxymethamphetamine must be avoided by using exclusively, as methylamine would lead to N-methylation; rigorous control of reagents and purification steps mitigates this. For commercial scale-up, the process employs continuous flow in large reactors, with purification via acid-base extraction and crystallization from or to isolate the salt at scales, ensuring compliance with pharmaceutical standards.

History

Early development

4-Hydroxyamphetamine, also known as p-hydroxyamphetamine, emerged in the during the as a sympathomimetic agent derived from analogs. It was first synthesized around as part of early investigations into sympathomimetic amines. Early investigations focused on its potential as a nasal and pressor agent, with initial clinical testing reported in using hydroxyamphetamine (Paredrine) as a spray for upper respiratory conditions, demonstrating its vasoconstrictive effects comparable to those of other sympathomimetics. These studies highlighted its ability to mimic epinephrine's actions on alpha-adrenergic receptors, though with a more indirect mechanism involving catecholamine release rather than direct . In the and , researchers explored its mydriatic potential through topical application, noting pupil dilation in animal models and human subjects as a result of norepinephrine release from postganglionic sympathetic neurons. Preclinical during this period demonstrated that 4-hydroxyamphetamine induced significant norepinephrine efflux from sympathetic nerve endings, leading to ocular effects such as and elevated , which were less pronounced than those of direct agonists like epinephrine but sustained due to its releasing properties. These findings positioned it as a useful tool for assessing sympathetic function in the eye, with comparisons to epinephrine underscoring its role in indirect sympathomimetic activity. Naming conventions during this period standardized it as p-hydroxyamphetamine or hydroxyamfetamine, distinguishing it from other amphetamine derivatives in pharmacological literature. By the , metabolic studies revealed 4-hydroxyamphetamine's significance as a key of in humans, with research detecting its presence in urine following amphetamine administration, confirming aromatic as a primary pathway. These investigations, building on earlier animal data, quantified its excretion as conjugated 4-hydroxyamphetamine, accounting for a notable portion of amphetamine's and contributing to its overall sympathomimetic profile.

Commercial introduction and availability

4-Hydroxyamphetamine was first commercialized in the mid-20th century as Paredrine, a 1% hydroxyamphetamine hydrobromide ophthalmic solution developed by Smith Kline & French Laboratories for inducing mydriasis in diagnostic eye examinations. In the 1990s, a combination formulation known as Paremyd—containing 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide—was introduced by Allergan Inc. to provide faster-onset pupil dilation compared to hydroxyamphetamine alone, with a marketing start date of January 30, 1992. A nationwide shortage of hydroxyamphetamine-based products, including Paredrine and Paremyd, occurred in the early due to raw material supply disruptions, leading to their temporary removal from the U.S. market. In 1998, Inc. acquired the rights to both brands from ; the company resolved the by reintroducing Paremyd in March 2002 as a faster-acting mydriatic option. As of 2025, Paremyd continues to face availability challenges stemming from ongoing manufacturing delays at , which halted production following its 2023 bankruptcy and shutdown. Paredrine is no longer commercially manufactured and is typically prepared on-demand by compounding pharmacies for limited neuro-ophthalmic applications. Internationally, distribution remains restricted due to the drug's niche diagnostic role, with approvals noted in select markets such as the by 2004, though global supply is minimal. Current production is primarily handled by specialized pharmaceutical firms, with heightened discontinuation risks for legacy brands amid vulnerabilities.

Society and culture

Nomenclature

The generic name for 4-hydroxyamphetamine is hydroxyamphetamine, with the (INN) designated as hydroxyamfetamine. The systematic IUPAC name is 4-(2-aminopropyl)phenol, equivalently expressed as 1-(4-hydroxyphenyl)propan-2-amine or 4-(1-methyl-2-aminoethyl)phenol in . Other synonyms include 4-hydroxy-α-methylphenethylamine and p-hydroxyamphetamine. Brand names include Paremyd for the combination product with tropicamide, manufactured by . The standalone formulation was formerly marketed as Paredrine but is no longer commercially available and is now prepared as a compounded 1% ophthalmic solution by some pharmacies. In international contexts, the INN hydroxyamfetamine is used alongside abbreviations such as 4-HA or p-OHA in scientific literature. In the United States, 4-Hydroxyamphetamine is classified as a prescription-only (℞) medication under FDA regulations, primarily available as an ophthalmic solution in products like Paremyd for diagnostic mydriasis. It is not federally scheduled as a controlled substance by the DEA, unlike amphetamine itself, which is Schedule II. However, it is listed as a controlled substance in select state schedules, such as Alabama's state-controlled list (Schedule I, as of January 16, 2025), where it falls under provisions for amphetamine derivatives. Under DEA considerations, 4-Hydroxyamphetamine may be treated as a analog in non-medical abuse contexts due to its structural and pharmacological similarity to , invoking the for prosecution if intended for human consumption outside approved uses. Prescription guidelines restrict its use primarily to ophthalmologists for eye examinations, with requirements for patient monitoring to prevent misuse given its sympathomimetic properties. Internationally, 4-Hydroxyamphetamine is regulated as a prescription-only medicinal product in regions with controls on sympathomimetics, such as the under pharmaceutical laws. As of November 2025, no major regulatory changes specific to this compound have been reported since 2020. 4-Hydroxyamphetamine is structurally and pharmacologically related to several compounds in the family.
  • Amphetamine: The parent compound, from which 4-hydroxyamphetamine is primarily metabolized via CYP2D6-mediated para-hydroxylation.
  • Methamphetamine: A precursor that also metabolizes to 4-hydroxyamphetamine, sharing similar sympathomimetic effects.
  • 4-Hydroxynorephedrine (p-Hydroxynorephedrine): A β-hydroxylated of amphetamine, exhibiting related noradrenergic activity.
  • Pholedrine (4-Hydroxymethamphetamine): An N-methylated analog used historically as a .
  • Norephedrine (Phenylpropanolamine): Another of amphetamine, with sympathomimetic properties.
  • 3-Hydroxyamphetamine: The meta-isomer , less potent in norepinephrine release.
These compounds share mechanisms involving trace amine-associated receptor 1 () agonism and catecholamine release, though 4-hydroxyamphetamine is distinguished by its primary use in ophthalmic applications.

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