Cognitive Effects of MDMA in Laboratory Animals: A Systematic Review Focusing on Dose

Abstract

Methylenedioxymethamphetamine (MDMA) is a synthetic, psychoactive drug that is primarily used recreationally but also may have some therapeutic value. At low doses, MDMA produces feelings of relaxation, empathy, emotional closeness, and euphoria. Higher doses can produce unpleasant psychostimulantand hallucinogen-like adverse effects and therefore are usually not taken intentionally. There is considerable evidence that MDMA produces neurotoxicity and cognitive deficits at high doses; however, these findings may not generalize to typical recreational or therapeutic use of low-dose MDMA. Here, we systematically review 25 years of research on the cognitive effects of MDMA in animals, with a critical focus on dose. We found no evidence that doses of less than 3 mg/kg MDMA-the dose range that users typically take-produce cognitive deficits in animals. Doses of 3 mg/kg or greater, which were administered most often and frequently ranged from 5 to 20 times greater than an average dose, also did not produce cognitive deficits in a slight majority of experiments. Overall, the preclinical evidence of MDMA-induced cognitive deficits is weak and, if anything, may be the result of unrealistically high dosing. While factors associated with recreational use such as polydrug use, adulterants, hyperthermia, and hyponatremia can increase the potential for neurotoxicity, the short-term, infrequent, therapeutic use of ultra low-dose MDMA is unlikely to pose significant cognitive risks. Future studies must examine any adverse cognitive effects of MDMA using clinically relevant doses to reliably assess its potential as a psychotherapeutic.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…3,4-Methylenedioxymethamphetamine. The debate on the neurotoxicity of MDMA creates a longstanding divide (Mithoefer et al, 2003;Parrott, 2013Parrott, , 2014Doblin et al, 2014;Pantoni and Anagnostaras, 2019;Ricaurte et al, 2002 [retracted]). Most of the available early preclinical research is focused on the neurotoxic effects of MDMA, which may explain cognitive impairments and psychiatric sequelae in MDMA abusers (Parrott, 2001(Parrott, , 2013.…”

“…Most of the available early preclinical research is focused on the neurotoxic effects of MDMA, which may explain cognitive impairments and psychiatric sequelae in MDMA abusers (Parrott, 2001(Parrott, , 2013. To simulate binge abuse and the resulting neurotoxic effects, relatively high doses (often in a chronic-administration design) were administered in these studies, with considerable neurotoxicity (Pantoni and Anagnostaras, 2019). Indeed, human studies indicate damaging effects on SERT homeostasis in heavy MDMA users (Baumann et al, 2007;Müller et al, 2019).…”

“…Indeed, human studies indicate damaging effects on SERT homeostasis in heavy MDMA users (Baumann et al, 2007;Müller et al, 2019). However, although these studies represent a valid paradigm for MDMA abuse, they do not seem to adequately model the sparing use of relatively low doses employed in MDMA-augmented psychotherapy (Amoroso, 2019;Pantoni and Anagnostaras, 2019), which elicits notable improvements in treatmentrefractory PTSD symptoms (Mithoefer et al, 2011(Mithoefer et al, , 2013Mithoefer et al, 2018;Feduccia et al, 2019;Bahji et al, 2020).…”

“…The existing lack of clear knowledge on potential neurotoxic effects of MDMA could be filled by employing realistic preclinical models that simulate clinically relevant pharmacodynamics (Pantoni and Anagnostaras, 2019;Vollenweider et al, 1999a). If further studies will determine that neurotoxic effects are elicited by MDMA administration in humans at clinically relevant doses, strategies could be implemented in an effort to protect against these effects (Tourino et al, 2010).…”

A Validated Method for the Simultaneous Determination of Methamphetamine and 3,4-Methylenedioxy-N-methamphetamine in Blood-Based Liquid Chromatography-Tandem Mass Spectrometry

“…MDMA has been shown to reduce the phenotypic expression of 5-HT throughout the adult brain [ 8 , 9 ]. Some evidence indicates the phenotype loss for MDMA-induced serotonin neurotoxicity in adults [ 10 , 11 ].…”