Propylhexedrine: a vintage drug of abuse, rediscovered.Propylhexedrine is a cycloalkylamine structurally similar to methamphetamine, the primary difference being the salicylic cyclohexyl group is present in lieu of an amphetamine's aromatic phenyl group (Wesson 1986). Like its amphetamine cousins, propylhexedrine is a chiral compound such that two stereoisomers are possible. The levorotatory isomer is the more active releaser of nor-epinephrine and dopamine in the central nervous system, and currently levopropylhexedrine is in fact synthesized from dextromethamphetamine (Wilson et al. 1971; Lands et al. 1947). The propylhexedrine contained in the Benzedrex inhalers is racemic D, L-propylhexedrine. Though the exact mechanism of action is unknown, propylhexedrine indirectly stimulates an adrenergic receptors of the sympathetic nervous system and exerts a minor stimulant effect on b adrenergic receptors (McEvoy 2007). In humans, it produces a pressor and stimulant effect similar to D-amphetamine, but less potent (WHO 1991, 1989). When the liquid is administered by inhalation it produces a local vasocontrictor effect prompting its therapeutic use as a decongestant. If converted to the crystalline propylhexedrine hydrochloride, it can then be crushed into a fine white powder and administered intranasally or dissolved in water for intravenous use (Smith et al. 1988; Fornazzari, Caarlen & Kapur 1986). Propylhexedrine is also quickly and well absorbed from the gastrointestinal tract after oral ingestion (Wesson 1986). Studies in mice have shown rapid passage across the blood brain barrier with maximum brain concentration paralleling plasma concentrations with a 10:1 brain/plasma ratio after intravenous administration (Ivan & Feldbusch 1983). When used by oral, intranasal, or intravenous routes, amphetamine-like intoxication symptoms, including euphoria, have been observed as well as signs of tolerance typical to stimulants of the central nervous system (WHO 1991, 1989; Wesson 1986).
A 33-year-old Caucasian male presented under court order for substance abuse treatment following his arrest for petit theft of Benzedrex inhalers from a local pharmacy. An initial psychiatric evaluation revealed a long history of stimulant abuse ranging from powder cocaine to large quantities of caffeine. In 2008, he began receiving Adderall prescriptions from a private primary care provider for the treatment of attention deficit hyperactivity disorder. The patient reported that at the peak of his drug abuse he was consuming a full one-month supply of Adderall, consisting of 90 20 mg tablets, over a seven-day period with the goal of achieving euphoria and increased energy. After two years of continuous abuse of Adderall, the patient's marriage had dissolved and he was unable to maintain employment. In the absence of medical coverage and a reliable source of income, Adderall prescriptions were no longer accessible. He began experiencing feelings of fatigue, depression, irritability and transient sensations of chest discomfort after stimulant intoxication had subsided. Despite growing concerns regarding adverse cardiac effects, he continued to invest all his efforts in finding a way to obtain stimulants. Apprehensive of trying to obtain illicit drugs off the street, he then turned to the Internet to search for an Adderall substitute that could be obtained over the counter. The search revealed a multitude of online drug forums not only recommending consumption of the Benzedrex cotton insert, but providing detailed instructions on how to chemically convert the propylhexedrine into "stove top speed" for snorting or intravenous use. Our patient found the small Benzedrex plastic nasal inhaler to contain an easily removable single cotton cylinder containing 250mg of propylhexadrine. Each OTC available inhaler cost just below $6, and they were also available online with free shipping for under $5 per inhaler. A pack of five inhalers (enough to make a gram of "stove top speed") cost only $25 in contrast to the average price of a gram of speed which has ranged from $127.28- to $278.97 (U.S. Department of Justice 2010). This patient opted to ingest the Benzedrex inserts directly, soaking it in a beverage to mask the odor, and swallowing it whole. The onset of effects was reported to occur within two to three minutes. Intoxication was heralded by flushing, muscle tension, and motor restlessness followed by feelings of increased heart rate, mood elevation and a sense of heightened focus and productive energy. After approximately three hours, the effects began to wane necessitating re-administration as many as four to five times per day. Inhaler use gradually escalated to more than eight cotton inserts per day. Due to financial strain, rather than cease use of Benzedrex, he moved in with a relative but within months he was having financial difficulty obtaining the quantity of Benzedrex needed to maintain intoxication. With resources exhausted, he resorted to stealing the inhalers from local pharmacies, culminating in his arrest. He was subsequently admitted for residential treatment of amphetamine dependence for four weeks where he benefited from a 12-Step facilitation treatment program.
In this case, DSM IV criteria for substance dependence were fulfilled. The patient demonstrated the need for increasing amounts of the substance to achieve the desired effect, important social and occupational roles were lost as the result of substance use, and use continued despite recurrent negative consequences. Though there have been no formal studies of the dependence potential of propylhexedrine, multiple case reports documenting the negative consequences of abuse, including pulmonary hypertension, myocardial infarction, psychotic reactions, ventricular arrhythmias, shock and death have been published since 1970 (Anderson 1970) and as recently as January 2011 (Holler et al. 2011). The number of case reports regarding propylhexedrine abuse has failed to exceed the threshold required by WHO to qualify as a significant abuse liability, with only 43 mentions of Benzedrex appearing in the Drug Abuse Warning Network between 1978 and 1982 (WHO 1991; Wesson 1986). However, the concern regarding propylhexedrine abuse was sufficient to warrant review by the Expert Committee on Drug Dependence on more than one occasion. The first review of propylhexedrine for scheduling was initiated by the WHO Expert Committee on Drug Dependence in 1985. It was given Schedule IV status based on stimulant actions (similar to amphetamines) and data showing adverse reactions occurring in cases of oral and intravenous abuse reported from 1974 to 1982 (WHO 1985). While case reports of oral and intravenous propylhexedrine abuse continued to be documented, incidence reports indicated that propylhexedrine was rarely used among chronic drug abusers as an alternative to amphetamines despite its easy availability (WHO 1991, 1989). Prior to 1991, there were only four reported cases of seizure of propylhexedrine from illegal drug laboratories where it was extracted from inhalers for the manufacture of what is colloquially known as "stove-top-speed" (Fornazzari, Carlen & Kapur 1986). The 1991 report by the WHO Expert Committee on Drug Dependence found that propylhexedrine had a reported low incidence of abuse and absence of any significant public health concerns; subsequently, propylhexedrine was classified an unscheduled substance in the United States and approved for over the-counter sale (WHO 1991).
The United States has long recognized that highly abused controlled substances could be manufactured with common, easily accessible household agents. Pseudoephedrine's use in the illegal manufacture of methamphetamine led to The Combat Methamphetamine Epidemic Acts of 2005 (CMEA) being signed into law on March 9, 2006. The CMEA regulated the sale of ephedrine, pseudo ephedrine, and phenylpropanolamine products with the goal of curtailing the production of methamphetamine in clandestine laboratories. The CMEA was careful to extend regulations to cover not only ephedrine, pseudo ephedrine, and phenylpropanolamine, but their salts, optical isomers, and salts of optical isomers as well. Pharmacies engaged in over-the-counter sales of products containing ephedrine, pseudoephedrine, or norpseudoephedrine were now required to store those products behind the pharmacy counter, check purchaser identification, and keep a formal records of sales including the number of grams purchased. As propylhexedrine is not chemically classified as amphetamine, it was not subject to those controls. A plethora of ancillary chemicals of interest not covered by the CMEA, but which were recognized as being used in the manufacture of controlled substances /illicit drugs were now reclassified and included in List I or II of chemicals in the Controlled Substances Act. Neither list contains propylhexedrine: the inhalers remain easily accessible either over the counter or online, and can be purchased individually or in bulk without a license or prescription.
Like its predecessor (amphetamine sulfate), inhalers containing propylhexedrine are being misused for the stimulant properties of its contents. The severe psychiatric and medical complications resulting from abuse of these inhalers raises the question of whether propylhexedrine is due for another review by the WHO Expert Committee to assess whether, as with ephedrine, control is necessary.
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Holler, J.M.; Vorce, S.P.; McDonough-Bender, P.C.; Magluilo, J. Jr.; Solomon, C.J. & Levine, B. 2011. A drug toxicity death involving propylhexedrine and mitragynine. Journal of Analytical Toxicology 35 (1): 54-9.
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Julia Paige Fernandez, M.D. (a) Elie M. Francis, M.D. (b)
(a) Resident Physician, University of South Florida Department of Psychiatry and Neurosciences, Tampa, FL.
(b) Staff Physician, Alcohol and Drug Abuse Treatment Program, Mental Health and Behavioral Health Sciences Service, James A. Haley Veterans' Hospital; Associate Professor, University of South Florida Department of Psychiatry and Neurosciences, Tampa, FL.
Please address correspondence to Julia Paige Fernandez, M.D., University of South Florida Department of Psychiatry and Neurosciences, 3515 E Fletcher Ave, MDC Box 14, Tampa, FL 33613; email: firstname.lastname@example.org