Michael D Berquist1, Sebastian Leth-Petersen2, Jesper Langgaard Kristensen2, William E Fantegrossi3. 1. Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham #611, Little Rock, AR, 72205, USA. 2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, København Ø, Denmark. 3. Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham #611, Little Rock, AR, 72205, USA. WEFantegrossi@uams.edu.
Abstract
RATIONALE: There is a renewed interest in the use of 3,4-methylenedioxymethamphetamine (MDMA) for treating psychiatric conditions. Although MDMA has entered phase II clinical trials and shows promise as an adjunct treatment, there is an extensive literature detailing the potential neurotoxicity and adverse neurobehavioral effects associated with MDMA use. Previous research indicates that the adverse effects of MDMA may be due to its metabolism into reactive catechols that can enter the brain and serve directly as neurotoxicants. One approach to mitigate MDMA's potential for adverse effects is to reduce O-demethylation by deuterating the methylenedioxy ring of MDMA. There are no studies that have evaluated the effects of deuterating MDMA on behavioral outcomes. OBJECTIVES: The purpose of the present study was to assess the motor-stimulant effects of deuterated MDMA (d2-MDMA) and compare them to MDMA in male mice. METHODS: Two experiments were performed to quantify mouse locomotor activity and to vary the drug administration regimen (single bolus administration or cumulative administration). RESULTS: The results of Experiments 1 and 2 indicate that d2-MDMA is less effective at eliciting horizontal locomotion than MDMA; however, the differences between the compounds diminish as the number of cumulative administrations increase. Both d2-MDMA and MDMA can elicit sensitized responses, and these effects cross-sensitize to the prototypical drug of abuse methamphetamine. Thus, d2-MDMA functions as a locomotor stimulant similar to MDMA, but, depending on the dosing regimen, may be less susceptible to inducing sensitization to stereotyped movements. CONCLUSIONS: These findings indicate that d2-MDMA is behaviorally active and produces locomotor effects that are similar to MDMA, which warrant additional assessments of d2-MDMA's behavioral and physiological effects to determine the conditions under which this compound may serve as a relatively safer alternative to MDMA for clinical use.
RATIONALE: There is a renewed interest in the use of 3,4-methylenedioxymethamphetamine (MDMA) for treating psychiatric conditions. Although MDMA has entered phase II clinical trials and shows promise as an adjunct treatment, there is an extensive literature detailing the potential neurotoxicity and adverse neurobehavioral effects associated with MDMA use. Previous research indicates that the adverse effects of MDMA may be due to its metabolism into reactive catechols that can enter the brain and serve directly as neurotoxicants. One approach to mitigate MDMA's potential for adverse effects is to reduce O-demethylation by deuterating the methylenedioxy ring of MDMA. There are no studies that have evaluated the effects of deuterating MDMA on behavioral outcomes. OBJECTIVES: The purpose of the present study was to assess the motor-stimulant effects of deuterated MDMA (d2-MDMA) and compare them to MDMA in male mice. METHODS: Two experiments were performed to quantify mouse locomotor activity and to vary the drug administration regimen (single bolus administration or cumulative administration). RESULTS: The results of Experiments 1 and 2 indicate that d2-MDMA is less effective at eliciting horizontal locomotion than MDMA; however, the differences between the compounds diminish as the number of cumulative administrations increase. Both d2-MDMA and MDMA can elicit sensitized responses, and these effects cross-sensitize to the prototypical drug of abuse methamphetamine. Thus, d2-MDMA functions as a locomotor stimulant similar to MDMA, but, depending on the dosing regimen, may be less susceptible to inducing sensitization to stereotyped movements. CONCLUSIONS: These findings indicate that d2-MDMA is behaviorally active and produces locomotor effects that are similar to MDMA, which warrant additional assessments of d2-MDMA's behavioral and physiological effects to determine the conditions under which this compound may serve as a relatively safer alternative to MDMA for clinical use.
Authors: Samuel Frank; Claudia M Testa; David Stamler; Elise Kayson; Charles Davis; Mary C Edmondson; Shari Kinel; Blair Leavitt; David Oakes; Christine O'Neill; Christina Vaughan; Jody Goldstein; Margaret Herzog; Victoria Snively; Jacquelyn Whaley; Cynthia Wong; Greg Suter; Joseph Jankovic; Joohi Jimenez-Shahed; Christine Hunter; Daniel O Claassen; Olivia C Roman; Victor Sung; Jenna Smith; Sarah Janicki; Ronda Clouse; Marie Saint-Hilaire; Anna Hohler; Denyse Turpin; Raymond C James; Ramon Rodriguez; Kyle Rizer; Karen E Anderson; Hope Heller; Alexis Carlson; Susan Criswell; Brad A Racette; Fredy J Revilla; Frederick Nucifora; Russell L Margolis; MaryJane Ong; Tilak Mendis; Neila Mendis; Carlos Singer; Monica Quesada; Jane S Paulsen; Thomas Brashers-Krug; Amanda Miller; Jane Kerr; Richard M Dubinsky; Carolyn Gray; Stewart A Factor; Elaine Sperin; Eric Molho; Mary Eglow; Sharon Evans; Rajeev Kumar; Christina Reeves; Ali Samii; Sylvain Chouinard; Monica Beland; Burton L Scott; Patrick T Hickey; Sherali Esmail; Wai Lun Alan Fung; Clare Gibbons; Lina Qi; Amy Colcher; Cory Hackmyer; Andrew McGarry; Kevin Klos; Mark Gudesblatt; Lori Fafard; Laura Graffitti; Daniel P Schneider; Rohit Dhall; Joanne M Wojcieszek; Kathrin LaFaver; Andrew Duker; Erin Neefus; Hilary Wilson-Perez; David Shprecher; Paola Wall; Karen A Blindauer; Lynn Wheeler; James T Boyd; Emily Houston; Eric S Farbman; Pinky Agarwal; Shirley W Eberly; Arthur Watts; Pierre N Tariot; Andrew Feigin; Scott Evans; Chris Beck; Constance Orme; Jon Edicola; Emily Christopher Journal: JAMA Date: 2016-07-05 Impact factor: 56.272
Authors: Rafael de la Torre; Magí Farré; Pere N Roset; Neus Pizarro; Sergio Abanades; Mireia Segura; Jordi Segura; Jordi Camí Journal: Ther Drug Monit Date: 2004-04 Impact factor: 3.681