Current Scheduling Status
None
Year(s) and type of review / ECDD meetings
Drug Class
Recommendation (from TRS)
ECDD Technical summary
A notification from the Government of the United States of America concerning the descheduling of propylhexedrine has been transmitted to WHO. Propylhexedrine is, at present, controlled under Schedule IV of the Convention on Psychotropic Substances, 1971. The first critical review of propylhexedrine that resulted in its scheduling was initiated by WHO, and was conducted at the twenty-second meeting of the WHO Expert Committee on Drug Dependence in 1985 (3), as part of a group of 28 stimulant phenethylamines. Propylhexedrine was subsequently reviewed at the twenty-fifth meeting of the Expert Committee (4), which examined the available information and noted little evidence of significant public health or social problems associated with propylhexedrine, especially in the USA, where it is readily available as an over-the-counter nasal inhaler preparation. It recommended, however, that no change be made in the scheduling of propylhexedrine but that the substance should be reviewed again in two years. At its present meeting, the Committee reviewed the past assessment of propylhexedrine as well as new information collected by the Secretariat and provided by the Government of the United States of America. Considering the revised WHO guidelines (1), the Committee focused especially on recent data on actual abuse and illicit activity. An updated review of propylhexedrine is presented below.
Substance identification
Propylhexedrine (INN; CAS 101-40-6) is chemically (+)-N,a-dimethylcyclohexaneethylamine. It has one chiral carbon atom in the molecule, so that two stereoisomeric forms and one racemate are possible.
Similarity to known substances and effects on the CNS
Animal pharmacological studies indicate that propylhexedrine has some stimulant actions, for example on locomotor activity, and pressor effects in common with amfetamine.
In humans, propylhexedrine produces pressor and stimulant effects similar to those of dexamfetamine but is significantly less potent. Administered by inhalation, propylhexedrine has local vasoconstrictor activity similar to that of ephedrine, but the duration of the activity is longer. Mucosal rebound congestion and chronic rhinitis may occur following excessive use of propylhexedrine in nasal inhalers. Amfetamine-like intoxication symptoms have been observed after oral or intravenous abuse.
Dependence potential
Studies in rats infused with propylhexedrine indicate that it acts as a typical stimulant of the central nervous system to which some tolerance develops. In drug-discrimination studies, propylhexedrine produced complete generalization to amfetamine in monkeys but only partial generalization in pigeons. It was self-administered by monkeys trained to self-administer cocaine, but at much lower response rates. There have been no controlled laboratory studies of the dependence potential of propylhexedrine in human subjects.
Actual abuse and or/evidence of likelihood of abuse
Oral and intravenous abuse of propylhexedrine has been documented over a period of about 30 years, usually in the form of single case reports.
Some of these reports mention severe adverse reactions after intravenous use, including myocardial infarction, "shock lung" syndrome, and death. Since 1988, when the Committee last reviewed propylhexedrine, more information has beceme aVailable on the incidence of abuse. People who abuse a variety of drugs on a chronic basis do not find the subjective effects of propylhexedrine very appealing and rarely bother to use it despite its easy availability. The Drug Abuse Warning Network in the USA reported two emergency-room and one medical examiner mentions for propylhexedrine from 1988 to 1989. Earlier data from the Drug Abuse Warning Network were also considered by the Committee. This network has not detected a significant amount of propylhexedrine abuse over the past 7 years. The threshold for inclusion in the list of "most frequently mentioned drugs" (which recently contained 256 drugs) is 10 reported episodes of abuse in any one year. Propylhexedrine did not exceed this threshold in 1983, 1984, 1986, 1987, 1988, or 1989. Since 1982, there have been only 50 mentions of propylhexedrine abuse out of a total of a million reported episodes of drug abuse. The Committee considered these mentions in relation to production within the USA and Canada of about 2500000 inhalers (approximately equivalent to 100 kg) annually, all of which were readily available over the counter. Since 1988, illicit traffic has been reported in only two countries. In the Federal Republic of Germany, only one prescription forgery was reported. In the USA, 4 cases involving propylhexedrine were reported: 3 cases primarily involving seizures of small amounts (a total of 8.8 g) of propylhexedrine from facilities described as "clandestine laboratories", and another involving 2 nasal inhalers. Based on these recent trends and the length of time that propylhexedrine has been available, the Committee concluded that propylhexedrine is not likely to be abused so as to constitute significant public health and social problems. However, the Committee considered it desirable not to make propylhexedrine available in over-the-counter forms other than inhalers.
Therapeutic usefulness
Propylhexedrine is used in an inhalant form for nasal decongestion. An oral formulation of the hydrochloride has been used as an anorectic agent in the treatment of obesity. A number of alternative drugs are available for both these indications. The Committee rated the therapeutic usefulness of propylhexedrine as low to moderate.
Recommendation
The Committee reviewed new documentary data indicating that the incidence of abuse and illicit trafficking was still very low and confirming the absence of any significant public health problems. Considering the revised WHO guidelines (/), the Committee recommended that propylhexedrine should be removed from international control under the Convention on Psychotropic Substances, 1971.
A notification from the Government of the United States of America concerning the descheduling of propylhexedrine has been transmitted to WHO. Propylhexedrine is, at present, controlled under Schedule IV of the Convention on Psychotropic Substances, 1971. The first critical review of propylhexedrine that resulted in its scheduling was initiated by WHO, and was conducted at the twenty-second meeting of the WHO Expert Committee on Drug Dependence in 1985 (3), as part of a group of 28 stimulant phenethylamines. Propylhexedrine was subsequently reviewed at the twenty-fifth meeting of the Expert Committee (4), which examined the available information and noted little evidence of significant public health or social problems associated with propylhexedrine, especially in the USA, where it is readily available as an over-the-counter nasal inhaler preparation. It recommended, however, that no change be made in the scheduling of propylhexedrine but that the substance should be reviewed again in two years. At its present meeting, the Committee reviewed the past assessment of propylhexedrine as well as new information collected by the Secretariat and provided by the Government of the United States of America. Considering the revised WHO guidelines (1), the Committee focused especially on recent data on actual abuse and illicit activity. An updated review of propylhexedrine is presented below.
Substance identification
Propylhexedrine (INN; CAS 101-40-6) is chemically (+)-N,a-dimethylcyclohexaneethylamine. It has one chiral carbon atom in the molecule, so that two stereoisomeric forms and one racemate are possible.
Similarity to known substances and effects on the CNS
Animal pharmacological studies indicate that propylhexedrine has some stimulant actions, for example on locomotor activity, and pressor effects in common with amfetamine.
In humans, propylhexedrine produces pressor and stimulant effects similar to those of dexamfetamine but is significantly less potent. Administered by inhalation, propylhexedrine has local vasoconstrictor activity similar to that of ephedrine, but the duration of the activity is longer. Mucosal rebound congestion and chronic rhinitis may occur following excessive use of propylhexedrine in nasal inhalers. Amfetamine-like intoxication symptoms have been observed after oral or intravenous abuse.
Dependence potential
Studies in rats infused with propylhexedrine indicate that it acts as a typical stimulant of the central nervous system to which some tolerance develops. In drug-discrimination studies, propylhexedrine produced complete generalization to amfetamine in monkeys but only partial generalization in pigeons. It was self-administered by monkeys trained to self-administer cocaine, but at much lower response rates. There have been no controlled laboratory studies of the dependence potential of propylhexedrine in human subjects.
Actual abuse and or/evidence of likelihood of abuse
Oral and intravenous abuse of propylhexedrine has been documented over a period of about 30 years, usually in the form of single case reports.
Some of these reports mention severe adverse reactions after intravenous use, including myocardial infarction, "shock lung" syndrome, and death. Since 1988, when the Committee last reviewed propylhexedrine, more information has beceme aVailable on the incidence of abuse. People who abuse a variety of drugs on a chronic basis do not find the subjective effects of propylhexedrine very appealing and rarely bother to use it despite its easy availability. The Drug Abuse Warning Network in the USA reported two emergency-room and one medical examiner mentions for propylhexedrine from 1988 to 1989. Earlier data from the Drug Abuse Warning Network were also considered by the Committee. This network has not detected a significant amount of propylhexedrine abuse over the past 7 years. The threshold for inclusion in the list of "most frequently mentioned drugs" (which recently contained 256 drugs) is 10 reported episodes of abuse in any one year. Propylhexedrine did not exceed this threshold in 1983, 1984, 1986, 1987, 1988, or 1989. Since 1982, there have been only 50 mentions of propylhexedrine abuse out of a total of a million reported episodes of drug abuse. The Committee considered these mentions in relation to production within the USA and Canada of about 2500000 inhalers (approximately equivalent to 100 kg) annually, all of which were readily available over the counter. Since 1988, illicit traffic has been reported in only two countries. In the Federal Republic of Germany, only one prescription forgery was reported. In the USA, 4 cases involving propylhexedrine were reported: 3 cases primarily involving seizures of small amounts (a total of 8.8 g) of propylhexedrine from facilities described as "clandestine laboratories", and another involving 2 nasal inhalers. Based on these recent trends and the length of time that propylhexedrine has been available, the Committee concluded that propylhexedrine is not likely to be abused so as to constitute significant public health and social problems. However, the Committee considered it desirable not to make propylhexedrine available in over-the-counter forms other than inhalers.
Therapeutic usefulness
Propylhexedrine is used in an inhalant form for nasal decongestion. An oral formulation of the hydrochloride has been used as an anorectic agent in the treatment of obesity. A number of alternative drugs are available for both these indications. The Committee rated the therapeutic usefulness of propylhexedrine as low to moderate.
Recommendation
The Committee reviewed new documentary data indicating that the incidence of abuse and illicit trafficking was still very low and confirming the absence of any significant public health problems. Considering the revised WHO guidelines (/), the Committee recommended that propylhexedrine should be removed from international control under the Convention on Psychotropic Substances, 1971.
ECDD Recommendation
Removal from the 1971 Convention on Psychotropic Substances
Link to full TRS
who_trs_808.pdf1.15 MB