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In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation.
Drug Alcohol Depend. 2020 03 01; 208:107850.DA

Abstract

BACKGROUND

Recent clinical studies support the use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct treatment for posttraumatic stress disorder (PTSD). Despite these promising findings, MDMA administration in controlled settings can increase blood pressure, heart rate, and body temperature. Previous studies indicate thatO-demethylated metabolites of MDMA contribute to its adverse effects. As such, limiting the conversion of MDMA to reactive metabolites may mitigate some of its adverse effects and potentially improve its safety profile for therapeutic use.

METHODS

We compared the interoceptive and hyperthermic effects of a deuterium-substituted form of MDMA (d2-MDMA) to MDMA using rodent drug discrimination and biotelemetry procedures, respectively.

RESULTS

Compared to MDMA, d2-MDMA produced full substitution for a 1.5 mg/kg MDMA training stimulus with equal potency and effectiveness in the drug discrimination experiment. In addition, d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA. Last, d2-MDMA and MDMA were equally effective in reversing the hypothermic effects of the selective 5-HT2A/2C antagonist ketanserin.

CONCLUSION

These findings indicate that deuterium substitution of hydrogen at the methylenedioxy ring moiety does not impact MDMA's interoceptive effects, and compared to MDMA, d2-MDMA has less potential for producing hyperthermic effects and likely has similar pharmacodynamic properties. Given that d2-MDMA produces less adverse effects than MDMA, but retains similar desirable effects that are thought to relate to the effective treatment of PTSD, additional investigations into its effects on cardiovascular functioning and pharmacokinetic properties are warranted.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham #611, Little Rock, AR, 72205, USA.Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark.Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark.Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham #611, Little Rock, AR, 72205, USA. Electronic address: WEFantegrossi@uams.edu.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

31954950

Citation

Berquist, Michael D., et al. "In Vivo Effects of 3,4-methylenedioxymethamphetamine (MDMA) and Its Deuterated Form in Rodents: Drug Discrimination and Thermoregulation." Drug and Alcohol Dependence, vol. 208, 2020, p. 107850.
Berquist MD, Leth-Petersen S, Kristensen JL, et al. In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation. Drug Alcohol Depend. 2020;208:107850.
Berquist, M. D., Leth-Petersen, S., Kristensen, J. L., & Fantegrossi, W. E. (2020). In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation. Drug and Alcohol Dependence, 208, 107850. https://doi.org/10.1016/j.drugalcdep.2020.107850
Berquist MD, et al. In Vivo Effects of 3,4-methylenedioxymethamphetamine (MDMA) and Its Deuterated Form in Rodents: Drug Discrimination and Thermoregulation. Drug Alcohol Depend. 2020 03 1;208:107850. PubMed PMID: 31954950.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation. AU - Berquist,Michael D, AU - Leth-Petersen,Sebastian, AU - Kristensen,Jesper Langgaard, AU - Fantegrossi,William E, Y1 - 2020/01/13/ PY - 2019/11/07/received PY - 2020/01/07/revised PY - 2020/01/08/accepted PY - 2020/1/20/pubmed PY - 2020/1/20/medline PY - 2020/1/20/entrez KW - 3,4-Methylenedioxymethamphetamine KW - Biotelemetry KW - Deuterated MDMA KW - Drug discrimination KW - Ketanserin KW - MDMA KW - d2-MDMA SP - 107850 EP - 107850 JF - Drug and alcohol dependence JO - Drug Alcohol Depend VL - 208 N2 - BACKGROUND: Recent clinical studies support the use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct treatment for posttraumatic stress disorder (PTSD). Despite these promising findings, MDMA administration in controlled settings can increase blood pressure, heart rate, and body temperature. Previous studies indicate thatO-demethylated metabolites of MDMA contribute to its adverse effects. As such, limiting the conversion of MDMA to reactive metabolites may mitigate some of its adverse effects and potentially improve its safety profile for therapeutic use. METHODS: We compared the interoceptive and hyperthermic effects of a deuterium-substituted form of MDMA (d2-MDMA) to MDMA using rodent drug discrimination and biotelemetry procedures, respectively. RESULTS: Compared to MDMA, d2-MDMA produced full substitution for a 1.5 mg/kg MDMA training stimulus with equal potency and effectiveness in the drug discrimination experiment. In addition, d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA. Last, d2-MDMA and MDMA were equally effective in reversing the hypothermic effects of the selective 5-HT2A/2C antagonist ketanserin. CONCLUSION: These findings indicate that deuterium substitution of hydrogen at the methylenedioxy ring moiety does not impact MDMA's interoceptive effects, and compared to MDMA, d2-MDMA has less potential for producing hyperthermic effects and likely has similar pharmacodynamic properties. Given that d2-MDMA produces less adverse effects than MDMA, but retains similar desirable effects that are thought to relate to the effective treatment of PTSD, additional investigations into its effects on cardiovascular functioning and pharmacokinetic properties are warranted. SN - 1879-0046 UR - https://www.unboundmedicine.com/medline/citation/31954950/In_vivo_effects_of_34_methylenedioxymethamphetamine__MDMA__and_its_deuterated_form_in_rodents:_Drug_discrimination_and_thermoregulation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0376-8716(20)30015-6 DB - PRIME DP - Unbound Medicine ER -
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