Methylone and MDMA Pharmacokinetics Following Controlled Administration in Humans

Abstract

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0–24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h*ng/mL and T1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10–14-fold lower and an AUC0–24 value that was 21–29-fold lower. Methylone pharmacokinetics was linear across 50–200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50–200 mg.

Sweat Testing for the Detection of Methylone after Controlled Administrations in Humans

“…Methylone was detectable in sweat at 2 h after the administration of all doses, corresponding to its peak concentration in plasma and oral fluid, and reached the highest concentration in sweat at 24 h, corresponding to the lowest methylone concentrations in plasma and oral fluid [ 2 , 20 ]. As expected, the main compound detected in sweat was the parent drug; the metabolite MDC was found at lower concentrations, while HMMC was not detected at any time interval.…”

“…Their structure is based on that of cathinone, a monoamine alkaloid found in the khat plant with psychoactive effects [ 1 ]. One of the most abused compounds of this class is 3,4-methylenedioxy-methcathinone (MDMC), more frequently known as methylone [ 2 ]. This drug often appears as a white powder [ 3 ].…”

“…Moreover, the reabsorption of MDMA from the skin was reported [ 12 ], and this may result in the continued presence of drugs on the skin surface also within time windows not covered by other biological matrices such as blood or urine. Several analytical methods for the determination of methylone in other matrices have been reported in the literature, such as in plasma and serum [ 2 ], urine [ 13 ], oral fluid [ 14 ] and hair [ 15 ]. However, to the best of our knowledge, no research in sweat has been yet published, nor pharmacokinetic studies involving this matrix.…”

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA

“…Methylone, a structural analog of MDMA, has emerged as a promising new treatment for PTSD. Methylone has been well-tolerated in several human studies ( Poyatos et al, 2021 , 2022 , 2023 ; Kelmendi et al, 2022 ; Averill et al, 2023 ; Jones et al, 2023 ), does not have hallucinogenic effects in humans ( Poyatos et al, 2021 ) or animal models ( Yu et al, 2023 , under review), and its potential efficacy has been demonstrated in two clinical case series of patients with PTSD ( Kelmendi et al, 2022 ) and MDD ( Averill et al, 2023 ). Recent data from an open-label study of methylone in 14 PTSD patients showed a 36.2 point reduction in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and no significant adverse events ( Jones et al, 2023 ).…”

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

“…To date, clinical experience with methylone has been described in four studies, which demonstrate that it is well tolerated, produces a milder range of effects compared with MDMA ( 11 , 12 ), and alleviates symptoms of PTSD in a retrospective clinical case series ( 13 ). It is notable that MDD and anxiety show high rates of comorbidity with PTSD ( 14 ), and SSRIs are used to treat all three disorders, suggesting that the reported effects of methylone in PTSD ( 13 ) may translate to therapeutic benefit in multiple CNS disorders.…”