Alternative names
4,4′-DMAR
IUPAC Name
4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine
Current Scheduling Status
Year(s) and type of review / ECDD meetings
Drug Class
Recommendation (from TRS)
Substance identification
Chemically, 4,4′-DMAR (para-methyl-4-methylaminorex) is 4-methyl-5- (4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine. 4,4′-DMAR has four enantiomers and exists as racemic cis- or trans- forms. It is a synthetic substituted oxazoline derivative interpretable as an analogue of 4-methylaminorex (4-MAR) and aminorex, which are psychostimulants listed as Schedule I and Schedule IV substances, respectively, under the 1971 United Nations Convention on Psychotropic Substances.
Previous review
4,4′-DMAR has not been previously reviewed by WHO. A critical review was proposed based on information brought to WHO’s attention that 4,4′-DMAR is clandestinely manufactured, poses a risk to public health and society, and has no recognized therapeutic use by any Party.
Similarity to known substances and effects on the central nervous system
In in vitro studies, cis-4,4′-DMAR demonstrates comparable potency to d-amphetamine and aminorex (which are scheduled under the 1971 United Nations Convention on Psychotropic Substances) to induce release of DA and NE, but with greater potency than those compounds to release 5-HT via their respective transporters. trans-4,4′-DMAR is also a fully efficacious releasing agent at the DAT and NET, but it acts as an uptake blocker at SERT. Currently, there are no published reports of clinical studies involving 4,4′-DMAR.
Dependence potential
There are no published animal or human studies that have examined the dependence and abuse potential of 4,4′-DMAR.
Actual abuse and/or evidence of likelihood of abuse
A seizure of 4,4′-DMAR was first reported in December 2012 in the Netherlands. Subsequently, use and seizures were reported in a number of other European countries. 4,4′-DMAR has been encountered as a "research chemical", in powdered and tablet form, and has been surreptitiously sold as "ecstasy" or other psychostimulant drugs. A total of 32 analytically confirmed deaths associated with 4,4′-DMAR have been reported. 4,4′-DMAR was found to contribute to the cause of death in a number of cases, despite the detection of one or more psychoactive substances and/or their metabolites in postmortem biological samples.
Therapeutic usefulness
There are currently no therapeutic applications for 4,4′-DMAR. Patent applications have been filed for some of its isomers that describe their uses as ligands for the trace amine associated receptor 1 (TAAR1) related to a range of potential applications to central nervous system disorders, and the (4S, 5S)- trans-4,4′-DMAR enantiomer has been featured in several patents related to the preparation of a range of phospholipase A2 inhibitors. There are no marketing authorizations (existing, ongoing or suspended) for 4,4′-DMAR.
Recommendation
As per the Guidance on the WHO review of psychoactive substances for international control (4), higher regard was accorded to the substantial public health risk than to the lack of therapeutic usefulness. The Committee considered that the degree of risk to public health and society associated with the abuse of 4,4′-DMAR is substantial. The Committee recommended that 4,4′-DMAR be placed in Schedule II of the 1971 Convention.
Chemically, 4,4′-DMAR (para-methyl-4-methylaminorex) is 4-methyl-5- (4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine. 4,4′-DMAR has four enantiomers and exists as racemic cis- or trans- forms. It is a synthetic substituted oxazoline derivative interpretable as an analogue of 4-methylaminorex (4-MAR) and aminorex, which are psychostimulants listed as Schedule I and Schedule IV substances, respectively, under the 1971 United Nations Convention on Psychotropic Substances.
Previous review
4,4′-DMAR has not been previously reviewed by WHO. A critical review was proposed based on information brought to WHO’s attention that 4,4′-DMAR is clandestinely manufactured, poses a risk to public health and society, and has no recognized therapeutic use by any Party.
Similarity to known substances and effects on the central nervous system
In in vitro studies, cis-4,4′-DMAR demonstrates comparable potency to d-amphetamine and aminorex (which are scheduled under the 1971 United Nations Convention on Psychotropic Substances) to induce release of DA and NE, but with greater potency than those compounds to release 5-HT via their respective transporters. trans-4,4′-DMAR is also a fully efficacious releasing agent at the DAT and NET, but it acts as an uptake blocker at SERT. Currently, there are no published reports of clinical studies involving 4,4′-DMAR.
Dependence potential
There are no published animal or human studies that have examined the dependence and abuse potential of 4,4′-DMAR.
Actual abuse and/or evidence of likelihood of abuse
A seizure of 4,4′-DMAR was first reported in December 2012 in the Netherlands. Subsequently, use and seizures were reported in a number of other European countries. 4,4′-DMAR has been encountered as a "research chemical", in powdered and tablet form, and has been surreptitiously sold as "ecstasy" or other psychostimulant drugs. A total of 32 analytically confirmed deaths associated with 4,4′-DMAR have been reported. 4,4′-DMAR was found to contribute to the cause of death in a number of cases, despite the detection of one or more psychoactive substances and/or their metabolites in postmortem biological samples.
Therapeutic usefulness
There are currently no therapeutic applications for 4,4′-DMAR. Patent applications have been filed for some of its isomers that describe their uses as ligands for the trace amine associated receptor 1 (TAAR1) related to a range of potential applications to central nervous system disorders, and the (4S, 5S)- trans-4,4′-DMAR enantiomer has been featured in several patents related to the preparation of a range of phospholipase A2 inhibitors. There are no marketing authorizations (existing, ongoing or suspended) for 4,4′-DMAR.
Recommendation
As per the Guidance on the WHO review of psychoactive substances for international control (4), higher regard was accorded to the substantial public health risk than to the lack of therapeutic usefulness. The Committee considered that the degree of risk to public health and society associated with the abuse of 4,4′-DMAR is substantial. The Committee recommended that 4,4′-DMAR be placed in Schedule II of the 1971 Convention.
ECDD Recommendation
Inclusion in Schedule II of the 1971 Convention on Psychotropic Substances
Link to full TRS
who_trs_998_eng.pdf330.66 KB
MS Questionnaire Report