Propylhexedrine

Propylhexedrine is used to treat acute nasal congestion related to the common cold, allergies, and hay fever. For nasal congestion, the dosage is listed as four inhalations (two inhalations per nostril) every two hours for adults and children 6–12 years of age. Each inhalation delivers 0.4 to 0.5 mg (400 to 500 μg) in 800 mL of air. Use is not to exceed three days.

Historically, it has also been used for weight loss in oral tablet preparations at a dose of 25 mg.{{cite journal | vauthors = Docherty JR | title = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | journal = British Journal of Pharmacology | volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124 }} No medications containing propylhexedrine are currently approved for weight loss in any country since roughly 1976.

Propylhexedrine should not be used if a MAOI has been used in the past 14 days or is currently in use by a person.

Unlike other topical decongestants, propylhexedrine is not required to carry a warning against use in individuals with hypertension.{{Cite journal | vauthors = Terrie YC |date=December 20, 2017 |title=Decongestants and Hypertension: Making Wise Choices When Selecting OTC Medications |url=https://www.pharmacytimes.com/view/decongestants-and-hypertension-making-wise-choices-when-selecting-otc-medications |url-status=live |archive-url=https://web.archive.org/web/20230130120554/https://www.pharmacytimes.com/view/decongestants-and-hypertension-making-wise-choices-when-selecting-otc-medications |archive-date=January 30, 2023 |access-date=November 13, 2023 |website=Pharmacy Times|series=December 2017 Heart Health |volume=83 }}

Propylhexedrine is not recommended in individuals younger than six years of age.{{Cite web |title=Propylhexedrine |url=https://www.mskcc.org/cancer-care/patient-education/medications/adult/propylhexedrine |archive-url=https://archive.today/20230809073320/https://www.mskcc.org/cancer-care/patient-education/medications/adult/propylhexedrine |archive-date=August 9, 2023 |access-date=2023-07-16 |website=www.mskcc.org |publisher=Memorial Sloan Kettering Cancer Center |language=en}} There is at least one case of reported accidental poisoning resulting from child access to a propylhexedrine product.

When used as an inhaler, the most common adverse effects warned about for propylhexedrine are temporary discomfort (e.g., stinging or burning sensations) or rebound congestion. The sharing of propylhexedrine inhalers may spread infection. The occurrence of these adverse effects is uncommon as propylhexedrine is generally recognized as safe and effective.{{Cite web |date=March 25, 2021 |title=Benzedrex (propylhexedrine): Drug Safety Communication |url=https://www.fda.gov/safety/medical-product-safety-information/benzedrex-propylhexedrine-drug-safety-communication-fda-warns-abuse-and-misuse-nasal-decongestant |archive-url=https://archive.today/20230807212835/https://www.fda.gov/safety/medical-product-safety-information/benzedrex-propylhexedrine-drug-safety-communication-fda-warns-abuse-and-misuse-nasal-decongestant |archive-date=August 7, 2023 |access-date=July 16, 2023 |website=FDA}} However, the use of propylhexedrine products in manners not intended by their labeling can result in severe adverse effects not typically encountered in therapeutic settings. The outcomes of improperly using propylhexedrine products can include hospitalization, disability, or even death. Public health agencies such as the Food and Drug Administration (FDA) have advised propylhexedrine products only be used in the manners directed on their label.

Reports of overdoses from propylhexedrine have been documented, but they are uncommon. Most instances of overdoses attributed to propylhexedrine have been the result of improper use of a propylhexedrine product in a manner not intended by its labeling for (non-medical) recreational purposes.{{Cite web |author=Center for Drug Evaluation and Research |date=2021-04-15 |title=FDA warns that abuse and misuse of the nasal decongestant propylhexedrine causes serious harm |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-abuse-and-misuse-nasal-decongestant-propylhexedrine-causes-serious-harm |url-status=dead |archive-url=https://web.archive.org/web/20230223010114/https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-abuse-and-misuse-nasal-decongestant-propylhexedrine-causes-serious-harm |archive-date=23 February 2023 |access-date=July 8, 2023 |website=FDA |publisher=U.S. Food and Drug Administration |language=en}} As noted by the FDA, the most common symptoms of propylhexedrine overdose are the following: "[r]apid heart rate, agitation, high blood pressure, chest pain, tremor, hallucinations, delusions, confusion, nausea, and vomiting." The use of propylhexedrine products in manners inconsistent with their labeling has proven fatal in some cases.{{Cite news |date=1985-09-22 |title=Rise In Nasal Inhaler Abuse Worries Officials |language=en-US |pages=34 |work=The New York Times |url=https://www.nytimes.com/1985/09/22/us/rise-in-nasal-inhaler-abuse-worries-officials.html |url-status=live |access-date=2023-08-30 |archive-url=https://archive.today/20230830042034/https://www.nytimes.com/1985/09/22/us/rise-in-nasal-inhaler-abuse-worries-officials.html |archive-date=August 30, 2023 |issn=0362-4331}} Propylhexedrine products are considered to be safe and effective if used as intended. Regardless, medical attention should be sought in the case of suspected overdose.

Most of propylhexedrine's interactions with other medications have to do with its ability to constrict blood vessels. Propylhexedrine’s most serious interaction is with monoamine oxidase inhibitors (MAOIs), which are contraindicated. Monoamine oxidase inhibitors are used, albeit uncommonly, as an antidepressant.{{Cite web |title=Monoamine oxidase inhibitors |url=https://www.mayoclinic.org/diseases-conditions/depression/in-depth/maois/art-20043992 |archive-url=https://archive.today/20220803044344/https://www.mayoclinic.org/diseases-conditions/depression/in-depth/maois/art-20043992 |archive-date=2022-08-03 |access-date=2024-05-15 |website=Mayo Clinic |language=en}} Nonetheless, caution should be exercised when administering propylhexedrine concurrently with other medicines.

Propylhexedrine works mainly as an adrenergic agonist, when used at therapeutic doses in an inhaler dosage form.{{cite web |title=Propylhexedrine |url=http://www.drugbank.ca/drugs/DB06714 |url-status=dead |archive-url=https://web.archive.org/web/20120315115006/http://www.drugbank.ca/drugs/DB06714 |archive-date=15 March 2012 |access-date=July 8, 2023 |work=DrugBank}} This restricts the blood vessels in the nose and reduces swelling; thereby, it relieves nasal congestion.{{Cite web |date=2017-10-18 |title=Decongestants |url=https://www.nhs.uk/conditions/decongestants/ |archive-url=https://archive.today/20230809064415/https://www.nhs.uk/conditions/decongestants/ |archive-date=August 9, 2023 |access-date=2023-08-09 |website=National Health Service |language=en}} At higher doses, propylhexedrine affects the central nervous system as a norepinephrine–dopamine releasing agent (NDRA). Propylhexedrine likely exerts such effects in a manner similar to related alkylamines such as cyclopentamine, methylhexanamine, and tuaminoheptane.{{cite journal | vauthors = Small C, Cheng MH, Belay SS, Bulloch SL, Zimmerman B, Sorkin A, Block ER | title = The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 386 | issue = 2 | pages = 266–273 | date = August 2023 | pmid = 37348963 | pmc = 10353075 | doi = 10.1124/jpet.122.001573 }}{{cite journal | vauthors = Schmidt JL, Fleming WW | title = A Nonsympathomimetic Effect of Cyclopentamine and Beta-Mercaptoethylamine in the Rabbit Ileum | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 145 | pages = 83–86 | date = July 1964 | doi = 10.1016/S0022-3565(25)26827-6 | pmid = 14209515 }}{{cite journal | vauthors = Delicado EG, Fideu MD, Miras-Portugal MT, Pourrias B, Aunis D | title = Effect of tuamine, heptaminol and two analogues on uptake and release of catecholamines in cultured chromaffin cells | journal = Biochemical Pharmacology | volume = 40 | issue = 4 | pages = 821–825 | date = August 1990 | pmid = 2386550 | doi = 10.1016/0006-2952(90)90322-c }} Propylhexedrine also exhibits antihypotensive effects.{{cite journal | vauthors = Lands AM, Nash VL | title = The pharmacologic activity of N-methyl-beta-cyclohexyl-isopropylamine hydrochloride | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 89 | issue = 4 | pages = 382–385 | date = April 1947 | doi = 10.1016/S0022-3565(25)05868-9 | pmid = 20295519 | url = https://jpet.aspetjournals.org/content/89/3/382 | url-access = subscription }}

File:Propylhexedrine_metabolism.svg

Propylhexedrine undergoes metabolism via N-demethylation, C-oxidation, N-oxidation, dehydrogenation, and hydrolysis to form various metabolites such as norpropylhexedrine, cyclohexylacetoxime, cyclohexylacetone, and 4-hydroxypropylhexedrine.{{cite journal | vauthors = Midha KK, Beckett AH, Saunders A | title = Identification of the major metabolites of propylhexedrine in vivo (in man) and in vitro (in guinea pig and rabbit) | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 4 | issue = 10 | pages = 627–635 | date = October 1974 | pmid = 4428789 | doi = 10.1080/00498257409169765 }}

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File:PropylhexedrineHCl.jpg salt of propylhexedrine. The off-brown color gives rise to the slang term for this salt: "peanut butter".{{cite journal | vauthors = Schaiberger PH, Kennedy TC, Miller FC, Gal J, Petty TL | title = Pulmonary hypertension associated with long-term inhalation of "crank" methamphetamine | journal = Chest | volume = 104 | issue = 2 | pages = 614–616 | date = August 1993 | pmid = 8101799 | doi = 10.1378/chest.104.2.614 }}]]

Freebase propylhexedrine is a volatile, oily liquid at room temperature. The slow evaporation of freebase propylhexedrine allows it to be administered via inhalation.{{cite patent|country=US|number=4095596|title=Nasal Inhaler|status=granted|gdate=20 June 1978|inventor=Grayson M |assign1=Smithkline Corp. | url = https://patents.google.com/patent/US4095596A/en }} The evaporation of the freebase also accounts for the limited shelf-life of propylhexedrine inhalers. Many of the salts of propylhexedrine are stable, clear to off-white crystalline substances that readily dissolve in water.{{cite journal | vauthors = Mancusi-Ungaro HR, Decker WJ, Forshan VR, Blackwell SJ, Lewis SR | title = Tissue injuries associated with parenteral propylhexedrine abuse | journal = Journal of Toxicology. Clinical Toxicology | volume = 21 | issue = 3 | pages = 359–372 | year = 1983 | pmid = 6144800 | doi = 10.1097/00005373-198307000-00114 }}

Propylhexedrine is similar in chemical structure to phenylethylamines. Phenylethylamines and substituted phenethylamines are found in the core of many trace amines and sympathomimetic drugs. The main difference is the presence of an alicyclic cyclohexyl group instead of the aromatic phenyl group of a phenethylamine.

:File:CycloalkylamineSim.svg

Propylhexedrine is a chiral compound. The active ingredient contained in Benzedrex inhalers is racemic (RS)-propylhexedrine as the free base. (S)-Propylhexedrine, also known as levopropylhexedrine, is the more biologically active isomer of the two. The dextrorotatory counterpart, which is mainly unused, is dextropropylhexedrine.

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Propylhexedrine can be synthesized from cyclohexylacetone through the reductive amination of an intermediary imine over an aluminum-mercury amalgam in the presence of a hydrogen source.{{cite book | vauthors = Lednicer D, Mitscher LA |title=Organic Chemistry of Drug Synthesis |date=1977 |publisher=Wiley |isbn=978-0-471-52141-9 |volume=1 |location=New York, NY |page=37}}

:File:Propylhexedrine synthesis from cyclohexylacetone.svg

However, propylhexedrine is more commonly prepared by the catalytic hydrogenation of methamphetamine over Adams' catalyst. This transforms methamphetamine's phenyl ring to a cyclohexyl moiety.{{cite journal | vauthors = Zenitz BL, Macks EB, Moore ML | title = Preparation of some primary and secondary beta-cyclohexylalkylamines | journal = Journal of the American Chemical Society | volume = 69 | issue = 5 | pages = 1117–1121 | date = May 1947 | pmid = 20240502 | doi = 10.1021/ja01197a039 | bibcode = 1947JAChS..69.1117Z }}

:File:Propylhexedrine synthesis.svg

The selective synthesis of enantiopure levopropylhexedrine can be accomplished through the initial Wenker synthesis of an intermediate aziridine followed by catalytic hydrogenation.{{Cite journal |last=Haberl |first=R. |date=1958-11-01 |title=Über eine neue Bildungsweise des 1,2-Dimethyl-3-phenyl-äthylenimins |trans-title=On a new mode of formation of 1,2-dimethyl-3-phenyl-ethylenimines |url=https://doi.org/10.1007/BF00902540 |journal=Monatshefte für Chemie und verwandte Teile anderer Wissenschaften |language=de |volume=89 |issue=6 |pages=814–816 |doi=10.1007/BF00902540 |issn=1434-4475|url-access=subscription }}

:File:Synthesis of levopropylhexedrine.svg

Administration of propylhexedrine can lead to false positives for phenethylamine derivatives on urinalysis panels.{{cite journal | vauthors = Thurman EM, Pedersen MJ, Stout RL, Martin T | title = Distinguishing sympathomimetic amines from amphetamine and methamphetamine in urine by gas chromatography/mass spectrometry | journal = Journal of Analytical Toxicology | volume = 16 | issue = 1 | pages = 19–27 | date = 1992 | pmid = 1640694 | doi = 10.1093/jat/16.1.19 }} Propylhexedrine can be differentiated upon further analysis.{{Cite journal | vauthors = Johnson P, Briner RC |date=October 1992 |title=A Clandestine Laboratory Extracting Propylhexedrine from Benzedrex Inhalers |url=https://bitnest.netfirms.com/external/JCLIC/2.4.25-28 |url-status=dead |journal=Journal of the Clandestine Laboratory Investigating Chemists Association |volume=2 |issue=4 |pages=25–28 |archive-url=https://web.archive.org/web/20230809075022/https://bitnest.netfirms.com/external/JCLIC/2.4.25-28 |archive-date=2023-08-09}}

Propylhexedrine's medical use as a decongestant evolved from desires to find safer alternatives to previous agents.{{Cite web | vauthors = Schwarez J |title=Sniffing Benzedrine Inhalers |url=https://www.mcgill.ca/oss/article/medical-health-and-nutrition/sniffing-benzedrine-inhalers |url-status=dead |archive-url=https://ghostarchive.org/archive/20230716000721/https://www.mcgill.ca/oss/article/medical-health-and-nutrition/sniffing-benzedrine-inhalers |archive-date=16 July 2023 |access-date=July 15, 2023 |website=Office for Science and Society |publisher=McGill University |language=en }} After searching for such an agent, Dr. Glenn E. Ullyot patented propylhexedrine as a decongestant in 1948. This patent was issued for benefit of Smith, Kline & French.{{Cite patent|country=US|number=2454746A|title=Cyclohexylalkylamines|gdate=1948-11-23|inventor=Ullyot GE|url=https://archive.today/20250114164621/https://patents.google.com/patent/US2454746A/en|assign=Smith Kline and French Laboratories Ltd.}} Before it was sold nationally in the United States, propylhexedrine underwent market trials in California. These market trials began on July 15, 1949. Propylhexedrine (under the brand name Benzedrex) was first introduced into commerce on August 4, 1949.{{Cite web | vauthors = Grant G |date=August 4, 1949 |title=Extension of remarks by representative Grant on H.R. 2969 - Bezedrine Inhalers |url=https://www.govinfo.gov/content/pkg/GPO-CRECB-1949-pt15/pdf/GPO-CRECB-1949-pt15-1.pdf |url-status=live |archive-url=https://web.archive.org/web/20231029071225/https://www.govinfo.gov/content/pkg/GPO-CRECB-1949-pt15/pdf/GPO-CRECB-1949-pt15-1.pdf |archive-date=October 29, 2023 |access-date=October 29, 2023 |website=Govinfo.gov |series=Volume 95 Issue 15 |publisher=Government Publishing Office |page=A5052 |via=the Congressional Record }}

File:Benzedrex-SKF.jpg that includes the synonym "1-cyclohexyl-2-methylaminopropane"]]

Approval for use in the United Kingdom soon followed in 1956. Later, approval for use in Canada was granted in 1998.{{Cite web |title=Propylhexedrine - NAPRA |url=https://www.napra.ca/nds/propylhexedrine/ |archive-url=https://archive.today/20230715190812/https://www.napra.ca/nds/propylhexedrine/ |archive-date=July 15, 2023 |access-date=2023-07-15 |website=(Canadian) National Association of Pharmacy Regulatory Authorities |language=en-US}} In 2023, B. F. Ascher & Co. decreased the amount of propylhexedrine in the Benzedrex inhaler from its historic 250 milligrams down to 175 milligrams.{{Cite web |title= BENZEDREX- propylhexedrine inhalant (06/23/2023) |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00d8c237-3eee-1d9f-e063-6394a90aeb86 |url-status=live |archive-url=https://archive.today/20231030224908/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00d8c237-3eee-1d9f-e063-6394a90aeb86 |archive-date=October 30, 2023 |access-date=2023-10-30 | work = Daily Med |publisher=U.S. National Library of Medicine}}

Barbexaclone, an anticonvulsant containing propylhexedrine, was used in Turkey until its withdrawal from the market in 2009. Barbexaclone's former niche in Turkish medicine is now largely occupied by levetiracetam.{{cite journal | vauthors = Bolukbasi F, Delil S, Bulus E, Senturk A, Yeni N, Karaagac N | title = End of the barbexaclone era: an experience of treatment withdrawal | journal = Epileptic Disorders | volume = 15 | issue = 3 | pages = 311–313 | date = September 2013 | pmid = 23981808 | doi = 10.1684/epd.2013.0605 | s2cid = 39112148 }}

The manufacture of propylhexedrine products for therapeutic use is typically performed based on guidelines established in government regulations and pharmacopeia monographs.{{Cite web |date=September 9, 1976 |title=Federal Register Vol. 41, No. 176 |url=https://www.govinfo.gov/content/pkg/FR-1976-09-09/pdf/FR-1976-09-09.pdf |archive-url=https://web.archive.org/web/20230716082330/https://www.govinfo.gov/content/pkg/FR-1976-09-09/pdf/FR-1976-09-09.pdf |archive-date=July 16, 2023 |website=Government Publishing Office |pages=38402}}{{Cite web |title=USP Monographs: Propylhexedrine Inhalant |url=https://doi.usp.org/USPNF/USPNF_M71100_01_01.html |url-status=dead |archive-url=https://web.archive.org/web/20231227063903/https://doi.usp.org/USPNF/USPNF_M71100_01_01.html |archive-date=27 December 2023 |access-date=2023-12-27 |website=United States Pharmacopeia }}

The illicit manufacture or diversion of propylhexedrine by clandestine chemists for use as a recreational drug has been documented in academic literature. Similar to when opioids are manufactured clandestinely for recreational use, it is unlikely that propylhexedrine produced by clandestine chemists adheres to the standards for purity, identity, and strength required of therapeutic products.{{cite journal | vauthors = Collier R | title = Street versions of opioids more potent and dangerous | journal = CMAJ | volume = 185 | issue = 12 | pages = 1027 | date = September 2013 | pmid = 23836854 | pmc = 3761004 | doi = 10.1503/cmaj.109-4535 }}

Propylhexedrine was placed under international control by the Convention on Psychotropic Substances in 1985. This action was reversed in 1991.{{Cite web |date=September 28, 1990 |title=Expert Committee on Drug Dependence's Twenty-Seventh Report |url=https://apps.who.int/iris/bitstream/handle/10665/40616/WHO_TRS_808.pdf?sequence=1&isAllowed=y |url-status=live |archive-url=https://web.archive.org/web/20230810175114/https://apps.who.int/iris/bitstream/handle/10665/40616/WHO_TRS_808.pdf?sequence=1&isAllowed=y |archive-date=August 10, 2023 |access-date=July 3, 2023 |website=World Health Organization |publisher=Expert Committee on Drug Dependence}}

Propylhexedrine is an S4 substance in Australia.{{Cite web |title=Therapeutic Goods (Poisons Standard—June 2024) |url=https://www.health.nsw.gov.au:443/pharmaceutical/Pages/sch4d.aspx |url-status=dead |archive-url=https://archive.today/20240813153903/https://www.legislation.gov.au/F2024L00589/latest/text |archive-date=August 13, 2024 |access-date=August 13, 2024 |website=Australian Government |language=en}}

Propylhexedrine is a Class B1 substance in Brazil.{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control |url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}

Propylhexedrine was long reported to be a Schedule V substance in Canada.{{Cite web |title=Erowid Propylhexedrine (Benzedrex) Vault : Law |url=https://www.erowid.org/pharms/propylhexedrine/propylhexedrine_law.shtml |url-status=dead |archive-url=https://web.archive.org/web/20230716004820/https://www.erowid.org/pharms/propylhexedrine/propylhexedrine_law.shtml |archive-date=16 July 2023 |access-date=2023-07-15 |website=Erowid }} In 2022, this status changed and propylhexedrine has since been removed from control under the Controlled Drugs and Substances Act.{{Cite web |last=Government of Canada |first=Public Works and Government Services Canada |date=2022-08-31 |title=Canada Gazette, Part 2, Volume 156, Number 18: Order Amending Schedule V to the Controlled Drugs and Substances Act (Novel Fentanyl Precursors) |url=https://www.gazette.gc.ca/rp-pr/p2/2022/2022-08-31/html/sor-dors185-eng.html |url-status=live |archive-url=https://web.archive.org/web/20240331223724/https://www.gazette.gc.ca/rp-pr/p2/2022/2022-08-31/html/sor-dors185-eng.html |archive-date=2024-03-31 |access-date=2024-03-31 |website=Canada Gazette}}

Propylhexedrine is regulated as a prescription medicine in Germany.{{Cite web |title=Anlage 1 AMVV - Einzelnorm |url=https://www.gesetze-im-internet.de/amvv/anlage_1.html |url-status=dead |archive-url=https://archive.today/20151130183959/http://www.gesetze-im-internet.de/amvv/anlage_1.html |archive-date=November 30, 2015 |access-date=2023-07-16 |website=Bundestag}} Initially, propylhexedrine products were available over-the-counter. However, this changed in the 1970s and propylhexedrine is now regulated as a prescription product in Germany.

Propylhexedrine was formerly a Class C substance in the United Kingdom, but was deregulated in 1995.{{cite web |title=The Misuse of Drugs Act 1971 (Modification) Order 1995 |url=http://www.legislation.gov.uk/uksi/1995/1966/contents/made |archive-url=https://archive.today/20230807213717/https://www.legislation.gov.uk/uksi/1995/1966/article/2/made |archive-date=August 7, 2023 |access-date=15 June 2009 |publisher=Office of Public Sector Information}} Propylhexedrine was used recreationally during a brief period in the 1970s after increased government regulation on earlier decongestants.{{Cite web |date=2016-03-23 |title=The blanket drugs ban is necessary, but won't solve the bigger problem – as I know from personal experience |url=http://theconversation.com/the-blanket-drugs-ban-is-necessary-but-wont-solve-the-bigger-problem-as-i-know-from-personal-experience-56237 |archive-url=https://archive.today/20240430064109/http://theconversation.com/the-blanket-drugs-ban-is-necessary-but-wont-solve-the-bigger-problem-as-i-know-from-personal-experience-56237 |archive-date=2024-04-30 |access-date=2023-11-19 |website=The Conversation |language=en-US |vauthors=Wilson A}}

On the 4th of April 1988, propylhexedrine was designated a controlled substance (Schedule V) in the United States.{{cite web | vauthors = Lawn J |date=April 4, 1988 |title=Schedules of Controlled Substances: Placement of Propylhexedrine and Pyrovalerone into Schedule V |url=https://isomerdesign.com/Cdsa/FR/53FR10869.pdf |url-status=live |archive-url=https://ghostarchive.org/archive/20221228191210/https://isomerdesign.com/Cdsa/FR/53FR10869.pdf |archive-date=28 December 2022 |access-date=9 July 2022 |website=Isomer Design |publisher=Drug Enforcement Administration }} This was done to satisfy U.S. compliance with an international treaty. However, in 1991, this action was reversed and propylhexedrine was removed from control under the Controlled Substances Act. This was based on the opinion of the Drug Enforcement Administration that propylhexedrine did not warrant control.{{cite web | vauthors = Bonner R |date=December 3, 1991 |title=Schedules of Controlled Substances: Removal of Propylhexedrine From Control |url=https://isomerdesign.com/Cdsa/FR/56FR61372.pdf |url-status=live |archive-url=https://ghostarchive.org/archive/20221228191210/https://isomerdesign.com/Cdsa/FR/56FR61372.pdf |archive-date=28 December 2022 |access-date=9 July 2022 |website=Isomer Design |publisher=Drug Enforcement Administration }} The substance has remained unregulated under the Controlled Substances Act in the United States ever since. Furthermore, pursuant to DEA regulations, certain Benzedrex inhalers are specifically exempt from the Controlled Substances Act.{{Cite web |title=Sec. 1308.22 Excluded substances. |url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=1308.22 |archive-url=https://archive.today/20230531045652/https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=1308.22 |archive-date=May 31, 2023 |access-date=May 30, 2023 |website=Code of Federal Regulations |publisher=Drug Enforcement Administration}}{{Cite web | vauthors = Haislip G |date=January 11, 1989 |title=Excluded Non-narcotic Over-the-counter Substances |url=https://archives.federalregister.gov/issue_slice/1989/1/19/2099-2101.pdf#page=2 |archive-url=https://web.archive.org/web/20230627005235/https://archives.federalregister.gov/issue_slice/1989/1/19/2099-2101.pdf |archive-date=June 27, 2023 |access-date=June 26, 2023 |website=Federal Register |publisher=Drug Enforcement Administration }} Propylhexedrine remains regulated under the laws of several U.S. states. These states include the states of Alaska,{{Cite web |title=2014 Alaska Statutes :: Title 11 - Criminal Law :: Chapter 11.71 - Controlled Substances :: Article 02 - Standards and Schedules :: Sec. 11.71.180 Schedule VA. |url=https://law.justia.com/codes/alaska/2014/title-11/chapter-11.71/article-02/section-11.71.180 |archive-url=https://archive.today/20231222072102/https://law.justia.com/codes/alaska/2014/title-11/chapter-11.71/article-02/section-11.71.180 |archive-date=2023-12-22 |access-date=2023-12-22 |website=Justia Law |language=en}} Arizona,{{Cite web |title=2005 Arizona Revised Statutes - :: Revised Statutes §13-3401 Definitions |url=https://law.justia.com/codes/arizona/2005/title13/03401.html |archive-url=https://archive.today/20231222072833/https://law.justia.com/codes/arizona/2005/title13/03401.html |archive-date=2023-12-22 |access-date=2023-12-22 |website=Justia Law |language=en}} Florida,{{Cite web |title=2011 Florida Statutes :: TITLE XLVI — CRIMES :: Chapter 893 — Drug Abuse Prevention and Control :: 893.03 — Standards and schedules. |url=https://law.justia.com/codes/florida/2011/titlexlvi/chapter893/section893.03 |archive-url=https://archive.today/20231222073123/https://law.justia.com/codes/florida/2011/titlexlvi/chapter893/section893.03 |archive-date=2023-12-22 |access-date=2023-12-22 |website=Justia Law |language=en}} Georgia,{{Cite web |title=2022 Georgia Code :: Title 16 - Crimes and Offenses :: Chapter 13 - Controlled Substances :: Article 2 - Regulation of Controlled Substances :: Part 1 - Schedules, Offenses, and Penalties :: § 16-13-29.1. Nonnarcotic Substances Excluded From Schedules of Controlled Substances |url=https://law.justia.com/codes/georgia/2022/title-16/chapter-13/article-2/part-1/section-16-13-29-1/ |archive-url=https://archive.today/20231222073402/https://law.justia.com/codes/georgia/2022/title-16/chapter-13/article-2/part-1/section-16-13-29-1/ |archive-date=2023-12-22 |access-date=2023-12-22 |website=Justia Law |language=en}} Idaho,{{Cite web |title=2010 Idaho Code :: Title 37 Food, Drugs, and Oil :: Chapter 27 Uniform Controlled Substances :: Article Ii :: 37-2713 Schedule V. |url=https://law.justia.com/codes/idaho/2010/title37/t37ch27sect37-2713.html |archive-url=https://archive.today/20231222073801/https://law.justia.com/codes/idaho/2010/title37/t37ch27sect37-2713.html |archive-date=2023-12-22 |access-date=2023-12-22 |website=Justia Law |language=en}} Kansas,{{Cite web |title=2017 Kansas Statutes :: Chapter 65 Public Health :: Article 41 Controlled Substances :: 65-4113 Substances included in schedule V. |url=https://law.justia.com/codes/kansas/2021/chapter-65/article-41/section-65-4113/ |archive-url=https://archive.today/20231222074029/https://law.justia.com/codes/kansas/2017/chapter-65/article-41/section-65-4113/ |archive-date=2023-12-22 |access-date=2023-12-22 |website=Justia Law |language=en}} and Rhode Island.{{Cite web |title=2021 Rhode Island General Laws :: Title 21 - Food and Drugs :: Chapter 21-28 - Uniform Controlled Substances Act :: Section 21-28-2.08 - Contents of schedules. |url=https://law.justia.com/codes/rhode-island/2021/title-21/chapter-21-28/section-21-28-2-08/ |archive-url=https://archive.today/20231222074400/https://law.justia.com/codes/rhode-island/2021/title-21/chapter-21-28/section-21-28-2-08/ |archive-date=2023-12-22 |access-date=2023-12-22 |website=Justia Law |language=en}}

Multiple public health agencies (most notably within the United States) have warned against the recreational use of propylhexedrine and advised for its use only as directed by a product's labeling; nonetheless it has been reported, through the literature as early as 1959, that propylhexedrine products have been used for recreational purposes.{{Cite journal |vauthors=Rose W |date=September 1959 |title=Arzneimittelsucht durch Mißbrauch von sogenannten Appetitzüglern (Obesin) |trans-title=Drug addiction due to abuse of so-called appetite suppressants (Obesin) |journal=Archiv für Toxikologie |language=de |volume=17 |issue=5 |pages=331–335 |bibcode=1959ArTox..17..331R |doi=10.1007/BF00577633 |issn=1432-0738 |s2cid=31539217}} Recreational use is potentially fatal, its risks are magnified when administering the substance through injection means, and the adverse effects of recreational propylhexedrine are more severe when compared to related substances.{{cite journal | vauthors = Fornazzari L, Carlen PL, Kapur BM | title = Intravenous abuse of propylhexedrine (Benzedrex) and the risk of brainstem dysfunction in young adults | journal = The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques | volume = 13 | issue = 4 | pages = 337–339 | date = November 1986 | pmid = 2877725 | doi = 10.1017/S0317167100036696 | doi-access = free }}{{cite journal | vauthors = Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J, Solomon CJ, Levine B | title = A drug toxicity death involving propylhexedrine and mitragynine | journal = Journal of Analytical Toxicology | volume = 35 | issue = 1 | pages = 54–59 | date = January 2011 | pmid = 21219704 | doi = 10.1093/anatox/35.1.54 | doi-access = free }} The undesirable side effects of propylhexedrine at recreational doses are less tolerable compared to other substances that produce similar effects; consequently, propylhexedrine is less desirable for recreational use.{{Cite web |title=Propylhexedrine (Benzedrex) |url=https://www.poison.org/articles/propylhexedrine |url-status=dead |archive-url=https://ghostarchive.org/archive/20230716060703/https://www.poison.org/articles/propylhexedrine |archive-date=16 July 2023 |access-date=2023-07-16 |website=National Capital Poison Control |language=en }}{{cite journal | vauthors = Anderson ED | title = Propylhexedrine (Benzedrex) psychosis | journal = The New Zealand Medical Journal | volume = 71 | issue = 456 | pages = 302 | date = May 1970 | pmid = 5270979 | s2cid = 30786926 }}{{cite journal | vauthors = Sturner WQ, Spruill FG, Garriott JC | title = Two propylhexedrine-associated fatalities: Benzedrine revisited | journal = Journal of Forensic Sciences | volume = 19 | issue = 3 | pages = 572–574 | date = July 1974 | pmid = 4137337 | doi = 10.1520/JFS10213J }} The fact that propylhexedrine is less potent than comparable substances has also limited recreational use.{{Cite web | vauthors = Cooper D |title="Future Synthetic Drugs of Abuse" |url=https://www.erowid.org/library/books_online/future_synthetic/ |archive-url=https://web.archive.org/web/20230809071331/https://www.erowid.org/library/books_online/future_synthetic/ |archive-date=August 9, 2023 |access-date=2023-08-09 |website=Erowid |publisher=Drug Enforcement Administration }}{{cite journal | vauthors = Garriott JC | title = Editorial: Propylhexadrine - a new dangerous drug? | journal = Clinical Toxicology | volume = 8 | issue = 6 | pages = 665–666 | date = 1975 | pmid = 6189 | doi = 10.3109/15563657508990092 }} Even in areas with prevalent substance use, the use of propylhexedrine was reported as non-significant;{{cite journal | vauthors = Smith DE, Wesson DR, Sees KL, Morgan JP | title = An epidemiological and clinical analysis of propylhexedrine abuse in the United States | journal = Journal of Psychoactive Drugs | volume = 20 | issue = 4 | pages = 441–442 | date = 1988-10-01 | pmid = 2907528 | doi = 10.1080/02791072.1988.10472514 }} nonetheless, the recreational use of nasal decongestant,{{Cite news | vauthors = Curry B |date=September 5, 1985 |title=Abuse of Potentially Fatal Nasal Inhaler Medication by Injection Called Widespread |newspaper=LA Times |url=https://www.latimes.com/archives/la-xpm-1985-09-05-mn-24755-story.html |access-date=September 7, 2023 |archive-url=https://web.archive.org/web/20210509111800/https://www.latimes.com/archives/la-xpm-1985-09-05-mn-24755-story.html |archive-date=May 9, 2021 }} anorectic, and anticonvulsant preparations{{cite journal | vauthors = Darcın AE, Dilbaz N, Okay IT | title = Barbexaclone abuse in a cannabis ex-user | journal = Substance Abuse | volume = 31 | issue = 4 | pages = 270–272 | date = October 2010 | pmid = 21038181 | doi = 10.1080/08897077.2010.514246 | bibcode = 2010JPkR...31..270D | s2cid = 7076881 }} of propylhexedrine has been reported. The recreational use of propylhexedrine products has been on the rise since the early 2000s.{{cite journal | vauthors = Teja N, Dodge CP, Stanciu CN | title = Abuse, Toxicology and the Resurgence of Propylhexedrine: A Case Report and Review of Literature | journal = Cureus | volume = 12 | issue = 10 | pages = e10868 | date = October 2020 | pmid = 33178521 | pmc = 7652022 | doi = 10.7759/cureus.10868 | doi-access = free }}

In 2021, the Food and Drug Administration (FDA) issued the following warning in regard to recreational use of propylhexedrine products in manners inconsistent with their labeling:

{{Blockquote|text=...[T]he abuse and misuse of the over-the-counter (OTC) nasal decongestant propylhexedrine can lead to serious harm such as heart and mental health problems. Some of these complications, which include fast or abnormal heart rhythm, high blood pressure, and paranoia, can lead to hospitalization, disability, or death....Propylhexedrine is safe and effective when used as directed.}}

That same year, the Indian Health Service issued the following statement{{Cite web |date=2021 |title=Abuse and Misuse of Propylhexedrine Nasal Decongestant Causes Serious Harm |url=https://www.ihs.gov/nptc/pharmacovigilance/medication-safety-resources-archive/2021/abuse-and-misuse-of-propylhexedrine-nasal-decongestant-causes-serious-harm/ |archive-url=https://web.archive.org/web/20230528203228/https://www.ihs.gov/nptc/pharmacovigilance/medication-safety-resources-archive/2021/abuse-and-misuse-of-propylhexedrine-nasal-decongestant-causes-serious-harm/ |archive-date=May 28, 2023 |access-date=2023-11-03 |website=National Pharmacy & Therapeutics Committee |publisher=Indian Health Service |language=en}} in reference to the recreational use of propylhexedrine products:

{{Blockquote|text=Only use propylhexedrine according to the instructions on the package label. Do not use it in ways other than inhalation. Seek medical attention immediately{{nbs}}[...] by calling [emergency services] or Poison Control{{nbs}}[...] for anyone using propylhexedrine who experiences [any of the following:] [s]evere anxiety or agitation, confusion, hallucinations, or paranoia[,] [r]apid heartbeat or abnormal heart rhythm[,] [or] [c]hest pain or tightness[.]}}

A year later, in 2022, the U.S. Army published the following guidance{{Cite web | vauthors = Parrish A |date=October 26, 2022 |title=FDA issues drug misuse guidance |url=https://www.army.mil/article/261494/fda_issues_drug_misuse_guidance |archive-url=https://web.archive.org/web/20221130001549/https://www.army.mil/article/261494/fda_issues_drug_misuse_guidance |archive-date=November 30, 2022 |access-date=2023-11-13 |website=United States Army |language=en}} on propylhexedrine. The guidance states that recreational use of propylhexedrine is not permissible by service-members, can open its participants up to disciplinary action, and carries potentially fatal risks:

{{Blockquote|text=When disciplining a member for suspected use of any drug, it is important to consult [legal counsel] on how to proceed, [according to the Office of Drug Demand Reduction]{{nbs}}[...] This is especially important when the evidence supporting discipline consists of scientific reports and data that may require special assistance in their interpretation. In cases involving [propylhexedrine], legal consultation is highly recommended.}}

Put briefly, the FDA, Indian Health Service, and U.S.{{nbs}}Army all advise individuals not to use propylhexedrine products for recreational purposes.

Propylhexedrine, under the brand name Benzedrex, is sold online by retailers such as Amazon, eBay, and Walmart.{{Cite web |title=Benzedrex Inhaler |url=https://www.bfascher.com/products/benzedrex/ |url-status=dead |archive-url=https://web.archive.org/web/20230708192205/https://www.bfascher.com/products/benzedrex/ |archive-date=8 July 2023 |access-date=July 8, 2023 |website=B. F. Ascher and Company }} Propylhexedrine has been sold in some countries as an anorectic or as part of an anticonvulsant preparation; however, such products are not sold freely to consumers and require a physician's prescription.

File:Benzedrex.jpg

Propylhexedrine, as a nasal decongestant, is currently marketed under the brand name Benzedrex. The name was initially trademarked by Smith, Kline & French in 1944.{{Cite web |title=Benzedrex Trademark of B.F. Ascher & Company Inc - Registration Number 0896775 - Serial Number 72340742 |url= http://trademarks.justia.com/723/40/benzedrex-72340742.html |url-status=dead |archive-url= https://archive.today/20230716051433/https://trademarks.justia.com/723/40/benzedrex-72340742.html |archive-date=July 16, 2023 |access-date=2023-07-16 |website=Justia |language=en}} The brand was passed onto Menley James Laboratories (through a subsidiary, NuMark Laboratories) in 1990, and was finally acquired by B. F. Ascher & Co. in 1998.{{Cite web | vauthors = Robertson V |date=February 17, 2004 |title=Prince v. B.F. Ascher Company, Inc., 90 P.3d 1020 (Okla. Civ. App. 2004) |url=https://casetext.com/case/prince-v-bf-ascher-company-inc |url-status=live |archive-url=https://ghostarchive.org/archive/20230716060731/https://casetext.com/case/prince-v-bf-ascher-company-inc |archive-date=16 July 2023 |access-date=2023-07-16 |website=CaseText }}{{Cite web |date=March 1, 1999 |title=B.F. Ascher marks 50th year. |url= https://www.thefreelibrary.com/B.F.+Ascher+marks+50th+year.-a054082926 |archive-url= https://archive.today/20230809072522/https://www.thefreelibrary.com/B.F.+Ascher+marks+50th+year.-a054082926 |archive-date=August 9, 2023 |access-date=2023-08-09 |website=The Free Library |publisher=Chain Drug Review}}

File:Dristan_Inhaler.jpg ]]

Propylhexedrine was also sold in inhaler form by Whitehall Laboratories (Wyeth) under the Dristan brand name as an inhaler.{{Cite web |date=November 24, 1989 |title=Action in Respect of International Conventions on Narcotic Drugs and Psychotropic Substances |url=https://iris.who.int/bitstream/handle/10665/163484/EB85_23_eng.pdf?sequence=1 |archive-url=https://web.archive.org/web/20231029070234/https://iris.who.int/bitstream/handle/10665/163484/EB85_23_eng.pdf?sequence=1 |archive-date=October 29, 2023 |access-date=October 29, 2023 |website=World Health Organization }} In January 1966, propylhexedrine replaced mephentermine as the active ingredient in the product.{{cite journal | vauthors = Angrist BM, Schweitzer JW, Gershon S, Friedhoff AJ | title = Mephentermine psychosis: misuse of the Wyamine inhaler | journal = The American Journal of Psychiatry | volume = 126 | issue = 9 | pages = 1315–1317 | date = March 1970 | pmid = 5413209 | doi = 10.1176/ajp.126.9.1315 }} The Dristan inhaler has since been discontinued. Furthermore, Wyeth was acquired by Pfizer in 2009. All products currently sold under the Dristan brand are manufactured by Foundation Consumer Brands; Foundation Consumer Brands acquired the Dristan brand in 2020.{{Cite web |date=October 1, 2020 |title=Foundation Consumer Healthcare to Add Seven Over-the-Counter Brands to Expanding Portfolio of Healthcare Products |url=https://foundationch.com/assets/press-release/2020-10-01.pdf |archive-url=https://web.archive.org/web/20231113224757/https://foundationch.com/assets/press-release/2020-10-01.pdf |archive-date=November 13, 2023 |access-date=November 13, 2023 |website=Foundation Consumer Brands |publisher=Kelso & Company}} Foundation Consumer Brands is itself owned by Kelso & Company.

File:Obesin.jpg

Propylhexedrine has also seen use in Europe as an appetite suppressant, under the brand name Obesin.{{cite journal | vauthors = Wesson DR | title = Propylhexdrine | journal = Drug and Alcohol Dependence | volume = 17 | issue = 2–3 | pages = 273–278 | date = June 1986 | pmid = 2874970 | doi = 10.1016/0376-8716(86)90013-X }} Obesin has been referenced in literature dating back to the 1950s.{{cite journal | vauthors = Polster H | title = Über eine Vergiftung mit dem Appetitzügler Propylhexedrin "Obesin", bei einem 3 Ährigen Kinde | trans-title = About poisoning with the appetite suppressant propylhexedrine "Obesin" in a 3-year-old child | language = de | journal = Archiv für Toxikologie | volume = 20 | pages = 271–273 | date = February 1965 | issue = 5 | pmid = 14272412 | doi = 10.1007/BF00577551 | s2cid = 19812917 }} Obesin was manufactured by Fahlberg-List in East Germany from 1958 to around 1976. The discontinuation of Obesin was the result of increased regulatory restrictions on over-the-counter anorectics. These restrictions began to be imposed in 1974.{{Cite journal | vauthors = Winter E |date=1976 |title=Bemerkungen zu Drogenmißbrauch und -abhängigkeit vom Amphetamin- Typ unter besonderer Berücksichtigung des Amphetaminils (Aponeuron (R) ) |trans-title=Comments on amphetamine-type drug abuse and dependence with special reference to amphetaminil (Aponeuron) |url=https://www.jstor.org/stable/45253962 |journal=Psychiatrie, Neurologie und medizinische Psychologie |language=DE |volume=28 |issue=9 |pages=513–525 |jstor=45253962 |issn=0033-2739}} Fahlberg-List itself dissolved in 1995.

File:Maliasin.jpg) carton, {{circa|2002}} manufactured by Knoll Pharmaceuticals]]

Propylhexedrine (in the form of levopropylhexedrine) is a component in the anticonvulsant preparation barbexaclone. It is included for the purpose of offsetting the barbiturate-induced sedation from phenobarbital. Barbexaclone has been known under the brand name of Maliasin, manufactured by Abbott Laboratories, as early as 1965.{{cite journal | vauthors = Krueger HJ, Schwarz H | title = [Clinical Communication on the Therapy of Epilepsy With Maliasin] | journal = Die Medizinische Welt | volume = 14 | pages = 690–692 | date = April 1965 | pmid = 14276849 }}{{Cite web |title=MALIASIN Trademark - Registration Number 0797076 - Serial Number 72213021 |url=http://trademarks.justia.com/722/13/maliasin-72213021.html |url-status=dead |archive-url=https://web.archive.org/web/20230716060838/https://trademarks.justia.com/722/13/maliasin-72213021.html |archive-date=16 July 2023 |access-date=2023-07-16 |website=Justia |language=en }} Maliasin has also been manufactured by Knoll Pharmaceuticals; Knoll is a company acquired by Abbott Laboratories. In 2010, Abbott discontinued sale of its barbexaclone preparation in many countries.{{Cite web | vauthors = Serracchiani D |date=January 31, 2011 |title=Parliamentary question {{!}} Maliasin {{!}} P-001035/2011 {{!}} European Parliament |url=https://www.europarl.europa.eu/doceo/document/P-7-2011-001035_EN.html |url-status=dead |archive-url=https://ghostarchive.org/archive/20230716050714/https://www.europarl.europa.eu/doceo/document/P-7-2011-001035_EN.html |archive-date=16 July 2023 |access-date=2023-07-16 |website=European Parliament |language=en }}

Levopropylhexedrine has been used as an appetite suppressant under the brand name Eventin. Eventin's use has been documented as early as 1958.{{cite journal | vauthors = Hofer R, Locker A | title = [Therapeutic experiences with the appetite depressant eventin] | journal = Wiener Medizinische Wochenschrift | volume = 108 | issue = 14 | pages = 304–306 | date = April 1958 | pmid = 13558159 | url = https://pubmed.ncbi.nlm.nih.gov/13558159/ }}

{{reflist}}

{{Decongestants}}

{{Stimulants}}

{{Monoamine releasing agents}}

Category:Anorectics

Category:Cycloalkylalkylamines

Category:Cyclohexyl compounds

Category:Decongestants

Category:Norepinephrine-dopamine releasing agents

Category:Sympathomimetics

Category:Vasoconstrictors

Category:VMAT inhibitors