4,4'-DMAR had been linked to at least 31 deaths in Hungary, Poland, and the UK by February 2014, mostly when consumed in combination with other drugs.[5] Nineteen deaths linked to 4,4'-DMAR were reported in Northern Ireland in the same time period.[6]
In contrast to many other MRAs, 4,4'-DMAR is inactive as atrace amine-associated receptor 1 (TAAR1)agonist.[7] As a result, whereas many other MRAs may auto-inhibit and constrain their effects via TAAR1 agonism, this may not occur with 4,4'-DMAR.[7] The drug also shows very weak interactions with the serotonin5-HT2A and5-HT2C receptors, though appears to be inactive at the serotonin5-HT2B receptor.[7][8]
4,4'-DMAR is anAnlage II controlled substance in Germany as of May 2015[update].[22]
Sweden's public health agency suggested to classify 4,4'-DMAR as hazardous substance on November 10, 2014.[23]
4,4'-DMAR is also banned in the Czech Republic.[24]
4,4'-DMAR is a Schedule I controlled substance in the US as of November 8, 2021. It only received two public comments during its public commenting period prior to being scheduled.[25][26]
^abcdefghiMaier J, Mayer FP, Brandt SD, Sitte HH (October 2018)."DARK Classics in Chemical Neuroscience: Aminorex Analogues".ACS Chem Neurosci.9 (10):2484–2502.doi:10.1021/acschemneuro.8b00415.PMC6287711.PMID30269490.It has recently been shown that 4,4'-DMAR binds to monoamine transporters with higher affinities compared to monoamine receptors, albeit it has also been shown to bind to hDAT, hNET, hSERT and 5-HT2A and 5-HT2C receptors with relatively low affinities135 (see Table 1). Due to the lack of interaction with the trace amine-associated receptor 1 (TAAR1), 4,4'- DMAR is suspected to be unable to trigger the auto-inhibitory pathway that, for example, MDMA possesses at least in rodents135,183,184. [...] It has recently been shown that 4,4′-DMAR inhibits the vesicular monoamine transporter 2 (VMAT2; SLC18A2) with a potency similar to that of MDMA.135 Perturbed function of VMAT2 has been associated with neurotoxicity.224,225 [...] As mentioned before, in contrast to other amphetamine-type stimulants, 4,4′-DMAR does not interact with rat and mouse TAAR1 and therefore lacks the autoinhibitory pathway that attenuates monoamine release and mediates the neuroprotective effects.231,232 It has however been shown that many psychoactive compounds stimulate human TAAR1 less potently than the receptor's rodent counterparts.184 [...] While it has been shown that 4,4′-DMAR binds to the 5-HT2A and 5-HT2C receptors,135 receptor binding assays for 5-HT2B have not been conducted yet.
^abMaier J, Mayer FP, Luethi D, Holy M, Jäntsch K, Reither H, Hirtler L, Hoener MC, Liechti ME, Pifl C, Brandt SD, Sitte HH (August 2018). "The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters".Neuropharmacology.138:282–291.doi:10.1016/j.neuropharm.2018.06.018.PMID29908239.
^abcPartilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes".Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc(PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252).PMID11680410.RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.
^Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs".European Journal of Pharmacology.479 (1–3):23–40.doi:10.1016/j.ejphar.2003.08.054.PMID14612135.
^Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates".Curr Top Med Chem.6 (17):1845–1859.doi:10.2174/156802606778249766.PMID17017961.
