MDMA and memory, addiction, and depression: dose-effect analysis

Abstract

Rationale ±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that shows substantial promise as a psychotherapeutic agent. Still, there is some concern regarding its behavioral toxicity, and its dose-effect relationship is poorly understood. We previously explored the role of dose in the cognitive effects of MDMA in a systematic review of existing literature and found no evidence in animals that MDMA impairs memory at low doses (< 3 mg/kg) but mixed results at high doses (≥ 3 mg/kg). Since this review comprised mostly of single-dose studies and an assortment of methodologies, an empirical dose-ranging study on this topic is warranted. Objectives The current study aims to evaluate the conclusion from our systematic review that 3 mg/kg may be the threshold for MDMA-induced amnesia, and to further understand the dose-effect relationship of MDMA on behavioral assays of memory, addiction, and depression. Methods We systematically examined the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioral sensitization, conditioned place preference, and conditioned responding; and the Porsolt forced swim test in mice. Results High doses of MDMA (≥ 3 mg/kg) produced amnesia of fear conditioning memory, some evidence of an addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) had no effect on these behaviors. Conclusions The present dose-ranging study provides further evidence that 3 mg/kg is the threshold for MDMA-induced amnesia. These findings, in addition to our systematic review, demonstrate that careful selection of MDMA dose is critical. High doses (≥ 3 mg/kg) should likely be avoided due to evidence that they can produce amnesia and addiction. Conversely, there is little evidence to suggest that low doses, which are usually administered in clinical studies (approximately 1–2 mg/kg), will lead to these same adverse effects. Ultra-low doses (< 1 mg/kg) are likely even safer and should be investigated for therapeutic effects in future studies.

A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy

“…The psychological and physiological effects of MDMA are a result of a complex set of only partially understood interactions between the drug and multiple neurotransmitter pathways ( 69 ). MDMA readily crosses the blood-brain barrier and binds to multiple targets with varying affinity, producing its effects in a dose-dependent manner ( 78 ). Like other psychostimulants, MDMA (the [+] enantiomer) binds with high affinity to monoamine transporters; the drug has the greatest affinity for the norepinephrine transporter (NET; K M = 225 ± 113 nM), followed closely by the dopamine transporter (DAT; K M = 444 ± 227 nM) and the serotonin transporter (SERT; K M = 447 ± 197 nM) ( 79 ).…”

“…MDMA is also thought to bind directly to the dopamine D1 and D2, β-adrenergic, α2-adrenergic, serotonin 5HT2A, serotonin 5HT2B, and H1-histaminergic receptors. Activity at these receptors is relatively weak however, and it is not yet clear how interaction at these receptors contributes to the effects of the drug ( 78 , 84 , 85 ). Recent studies suggest that MDMA may also be active at the trace-amine associated receptor (TAAR1) and the Sigma-1 receptor as well ( 63 ).…”

MDMA and Their Analogs as Therapeutics for Mental Disorder and Response Predictor

“…The table below shows possible outcomes from patients with alcohol use disorder and conducting a treatment protocol comprising 14 psychotherapy sessions, wherein 3 of the 14 psychotherapy sessions are MDMA-assisted psychotherapy sessions. Each MDMA-assisted psychotherapy sessions includes an initial dose (100–150 mg) and an optional booster dose of about half the initial dose. …”

A review on the mitochondrial toxicity of “ecstasy” (3,4-methylenedioxymethamphetamine, MDMA)

“…MDMA human abuse and dependence is well described, but addictive properties are not always reported in a consistent manner across studies ( Cottler et al, 2009 ). Human and animal studies converge into the idea that higher doses are prone to evoke addition, meanwhile ultra-low doses (<1 mg/kg) seem safer ( Pantoni et al, 2022 ).…”