Synthetic psychoactive cathinones: hypothermia and reduced lethality compared to methamphetamine and methylenedioxymethamphetamine.

RATIONALE: Synthetic psychoactive cathinones (SPCs) are drugs with psychostimulant and entactogenic properties like methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA). Despite clinical reports of human overdose, it remains to be determined if SPCs have greater propensity for adverse effects than MA or MDMA. OBJECTIVES: To determine whether the SPCs cathinone (CAT), methcathinone (MCAT), mephedrone (MMC), and methylenedioxypyrovalerone (MDPV) have lower LD50 values than MA or MDMA. METHODS: Male and female C57Bl/6J mice received single injections of one of 6 doses of a test drug (0-160 mg/kg IP). Temperature and behavioral observations were taken every 20 min for 2 h followed by euthanasia of surviving mice. Organs were weighed and evaluated for histopathological changes. RESULTS: LD50 values for MA and MDMA, 84.5 and 100.9 mg/kg respectively, were similar to previous observations. The LD50 for MMC was 118.8 mg/kg, but limited lethality was observed for other SPCs (CAT, MCAT, MDPV), so LD50 values could not be calculated. For all drugs, death was associated with seizure, when it was observed. Rather than hyperthermia, dose-dependent hypothermia was observed for MMC, MDPV, CAT, and MCAT. Contrary to initial expectations, none of the SPCs studied here had LD50 values lower than MA or MDMA. CONCLUSIONS: These data indicate that, under the conditions studied here: (1) SPCs exhibit less lethality than MA and MDMA; (2) SPCs impair thermoregulation; (3) effects of SPCs on temperature appear to be independent of effects on lethality.

The Streetlight Effect: Reappraising the Study of Addiction in Light of the Findings of Genome-wide Association Studies.

Drug dependence has long been thought to have a genetic component. Research seeking to identify the genetic basis of addiction has gone through important transitions over its history, in part based upon the emergence of new technologies, but also as the result of changing perspectives. Early research approaches were largely dictated by available technology, with technological advancements having highly transformative effects on genetic research, but the limitations of technology also affected modes of thinking about the genetic causes of disease. This review explores these transitions in thinking about the genetic causes of addiction in terms of the "streetlight effect," which is a type of observational bias whereby people search for something only where it is easiest to search. In this way, the genes that were initially studied in the field of addiction genetics were chosen because they were the most "obvious," and formed current understanding of the biological mechanisms underlying the actions of drugs of abuse and drug dependence. The problem with this emphasis is that prior to the genomic era the vast majority of genes and proteins had yet to be identified, much less studied. This review considers how these initial choices, as well as subsequent choices that were also driven by technological limitations, shaped the study of the genetic basis of drug dependence. While genome-wide approaches overcame the initial biases regarding which genes to choose to study inherent in candidate gene studies and other approaches, genome-wide approaches necessitated other assumptions. These included additive genetic causation and limited allelic heterogeneity, which both appear to be incorrect. Thus, the next stage of advancement in this field must overcome these shortcomings through approaches that allow the examination of complex interactive effects, both gene × gene and gene × environment interactions. Techniques for these sorts of studies have recently been developed and represent the next step in our understanding of the genetic basis of drug dependence.