Methylone, a rapid acting entactogen with robust anxiolytic and antidepressant-like activity

This rat study finds that methylone (5-3-mg/kg) showed a reduction of 95% in immobility in the forced swim test (FST), a measure of antidepressant effects commonly used in mice studies. Methylone is similar to MDMA but shows less activity in the serotonin system. Pretreatment with an antidepressant (fluoxetine) didn’t change the effects, indicating they may be co-administrated.

Abstract

Introduction: Selective serotonin reuptake inhibitor (SSRI) antidepressants represent first-line pharmacological treatment for a variety of neuropsychiatric illnesses, including major depressive disorder (MDD), anxiety, and post-traumatic stress disorder (PTSD), which show high rates of comorbidity. SSRIs have a delayed onset of action. Most patients do not show significant effects until 4–8 weeks of continuous treatment, have impairing side effects and as many as 40% of patients do not respond. Methylone (3,4-methylenedioxy-N-methylcathinone; MDMC, βk-MDMA, M1) is a rapid-acting entactogen that showed significant benefit in a clinical case series of PTSD patients and was well-tolerated in two Phase 1 studies of healthy volunteers. Based on these early observations in humans, in the current study we tested the hypothesis that methylone has antidepressant-like and anxiolytic effects in preclinical tests.

Methods: For all studies, 6–8-week-old male Sprague Dawley rats (N = 6–16) were used. We employed the Forced Swim Test (FST), a classic and widely used screen for antidepressants, to explore the effects of methylone and to probe dose-response relationships, durability of effect, and potential interactions with combined SSRI treatment. We compared the effect of methylone with the prototypical SSRI fluoxetine.

Results: Three doses of fluoxetine (10 mg/kg) given within 24 h before FST testing caused a 50% reduction in immobility compared with controls that lasted less than 24 h. In contrast, a single dose of methylone (5–30 mg/kg) administered 30 min prior to testing produced a rapid, robust, and durable antidepressant-like response in the FST, greater in magnitude than fluoxetine. Immobility was reduced by nearly 95% vs. controls and effects persisted for at least 72 h after a single dose (15 mg/kg). Effects on swimming and climbing behavior in the FST, which reflect serotonergic and noradrenergic activity, respectively, were consistent with studies showing that methylone is less serotoninergic than MDMA. Fluoxetine pretreatment did not change methylone’s antidepressant-like effect in the FST, suggesting the possibility that the two may be co-administered. In addition, methylone (5–30 mg/kg) exhibited anxiolytic effects measured as increased time spent in the center of an open field.

Discussion: Taken together, and consistent with initial clinical findings, our study suggests that methylone may have potential for treating depression and anxiety.”

Authors: Jennifer Warner-Schmidt, Christopher Pittenger, Martin Stogniew, Blake Mandell, Sarah J. Olmstead & Benjamin Kelmendi

Study details

Topics studied
Depression Anxiety

Study characteristics
Animal Study

Participants
16 Rodents

Linked Research Papers

Notable research papers that build on or are influenced by this paper

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA
This preclinical study (in cells) investigated methylone's potential for treating PTSD, comparing it with MDMA. Methylone showed rapid antidepressant and anxiolytic effects in preclinical models, affecting gene expression related to neuroplasticity in brain areas associated with PTSD and MDD. Unlike MDMA, methylone demonstrated no off-target effects at various receptors, indicating potential higher specificity, and suggesting its potential use in treating PTSD and other neuropsychiatric disorders.

Pharmacological effects of methylone and MDMA in humans
This double-blind study (n=17) compared the pharmacological effects of methylone (200mg) and MDMA (100mg), for which methylone is a popular substitute. The results showed that methylone could significantly increase blood pressure and heart rate and induce pleasurable effects similar to MDMA, including stimulation, euphoria, well-being, enhanced empathy, and altered perception.

PDF of Methylone, a rapid acting entactogen with robust anxiolytic and antidepressant-like activity