Bath salts abuse has emerged as serious public health concern in the US. Bath salts are synthetic powders that are sold legally in commercial establishments and head-shops under such names as Ivory Wave, Red Dove or Scarface and they are promoted as legal or harmless highs. Bath salts are CNS stimulants and the active ingredients include cathinone, methcathinone, mephedrone, methylone and 3,4- methylenedioxypyrovalerone (MDPV). These agents are classified chemically as -ketoamphetamines (-KA). Emerging evidence of the high addictive potential and craving associated with the -KAs has set off alarms of concern at numerous US governmental agencies that monitor drug abuse trends to include NIDA, the White House Drug Czar, DEA and the Department of Justice. Almost as alarming as the rise in abuse of the -KAs is the paucity of data on their mechanisms of action and particularly their ability to damage the CNS. The structural analogy of the -KAs to their de-keto amphetamine congeners is striking- the only difference between these drugs is the lack of the -keto moiety on the amphetamines. Initial studies have indicated that the -KAs exert very mild if any neurotoxicity to dopamine and serotonin nerve endings but they significantly enhance methamphetamine neurotoxicity. This finding comes as a great surprise because many of the bath salts drugs possess those characteristics that are thought to be essential for methamphetamine neurotoxicity to include the coincident stimulation of DA release and inhibition of its uptake and catabolism, and elevations in core body temperature. The fact that mephedrone is not neurotoxic therefore offers an excellent opportunity to determine the structural features that render it inert (i.e., from a toxicty perspective) by comparison to the highly neurotoxic methamphetamine. The structure of mephedrone includes a beta-keto group and a methyl group at the 4-position. Methamphetamine lacks both. Therefore, one or both of these structural elements determines whether two essentially identical compounds are neurotoxic (i.e., methamphetamine) or non- neurotoxic (i.e., mephedrone). The structural intermediates (not metabolic) in the progression from mephedrone to methamphetamine are clear. If the 4-CH3 group of mephedrone is removed, the yield is methcathinone (MC). If the beta-keto group of mephedrone is removed, the yield is 4-methyl- methamphetamine (4-MM). A very small number of studies have shown that MC causes mild damage to DA and serotonin (5HT) nerve endings in rodents and abstinent human MC abusers have persistent reductions in the DAT, a possible sign of neuronal damage. 4-MM has not been studied in rodents or humans to the best of our knowledge. Therefore, the goal of studies in this CEBRA application is to assess the ability of MC and 4- MM to cause neurotoxicity to DA nerve endings. The relative contributions of the beta-keto and 4-CH3 groups to toxicity will emerge from these studies and offer an innovative view of the structural elements that mediate methamphetamine neurotoxicity.
This project is highly relevant to public health because it will determine the structural features of methamphetamine that make it neurotoxic. Mephedrone, an abused 'bath salts' drug, is very close in structure to methamphetamine but is not neurotoxic. The present studies will focus on the structural intermediates between mephedrone and methamphetamine- methcathinone and 4-methyl-methamphetamine- to determine how the -keto and 4-methyl substituents on mephedrone render it non-neurotoxic by comparison to methamphetamine, which lacks both.
