Abuse Potential and Human Pharmacology of Methylone

Brief Summary

The purposes of the study are 1) To assess the abuse potential of methylone after controlled administration of a single oral dose of methylone 2) to evaluate subjective and physiological effects of methylone 3) to determine the pharmacokinetics parameters and metabolism of methylone.

Intervention / Treatment

The protocol comprises a pilot study (n= 12) and a definitive study (n=17, 14 men and 3 women). The pilot study was a phase I dose-finding study that included 4 cohorts of 3 subjects (cohort 1,2,3 and 5). The conditions of each cohort were: 50 and 100 mg of methylone and placebo in cohort 1 (n= 3); 100 and 150 mg of methylone and placebo in cohort 2 (n= 3); 150 and 200 mg of methylone and placebo in cohort 3 (n= 3); 200 mg of methylone, 100 mg of MDMA and placebo in cohort 5 (n= 3). For safety reasons in cohorts 1-2-3, lower doses were allocated before the higher doses. After completion, the pilot study allowed defining the treatment conditions and interventions of the definitive study. The present definitive study was designed as double-blind, placebo-controlled, crossover and randomized. Each subject will participate in three experimental sessions, in each one treatment will be administered. Study treatment conditions are 200 mg of methylone, 100 mg of MDMA and placebo.
  • Methylone (DRUG)
    Single oral dose of 200 mg of methylone.
  • 3,4-methylenedioxymethamphetamine (DRUG)
    Single oral dose of 100 mg of MDMA.
  • Placebo (DRUG)
    Single oral dose of placebo.

Condition or Disease

  • Substance Use
  • Healthy Subjects

Phase

  • Phase 1

    • Study Design

    Study type: INTERVENTIONAL
    Status: Active, not recruiting
    Study results: No Results Available
    Age: 18 Years to 45 Years
    Enrollment: 17 (ACTUAL)
    Allocation: Randomized
    Primary Purpose: Basic Science

    Masking

    Identical white hard gelatin capsules

    QUADRUPLE:
    • Participant
    • Care Provider
    • Investigator
    • Outcomes Assessor

    Clinical Trial Dates

    Start date: Dec 01, 2021 ACTUAL
    Primary Completion: Jul 31, 2022 ACTUAL
    Completion Date: Sep 30, 2022 ESTIMATED
    Study First Posted: Aug 04, 2022 ACTUAL
    Last Updated: Aug 04, 2022

    Sponsors / Collaborators

    Lead Sponsor: N/A
    Lead sponsor is responsible party
    Responsible Party: N/A

    Methylone is a synthetic cathinone that has been popularized as an alternative to other illegal psychostimulants as methylenedioxymethamphetamine (MDMA, ecstasy) or mephedrone. Chemically, methylone is a beta-keto analogue of ecstasy with similar pharmacological effects in animals. To date, the available data about the human pharmacology of methylone in humans is very scarce and is mainly provided by users' experience published in internet forums or intoxication reports.

    A pilot study was carried out to select the methylone dose used in this study. This current study is aimed 1) To assess the abuse potential of methylone after controlled administration of a single oral dose of methylone 2) to evaluate subjective and physiological effects of methylone 3) to determine the pharmacokinetics parameters and metabolism of methylone.

    Participant Groups

    • Methylone (3,4-methylenedioxy-N-methylcathinone) 200 mg, single dose, oral administration

    • MDMA (3,4-methylenedioxymethamphetamine) 100 mg, single dose, oral administration

    • Placebo, single dose, oral administration

    Eligibility Criteria

    Sex: All
    Minimum Age: 18
    Maximum Age: 45
    Age Groups: Adult
    Healthy Volunteers: Yes

    Inclusion Criteria:

    * Understanding and accepting all the study procedures and signing the informed consent.
    * Healthy male and female volunteers aged between 18 and 45.
    * Clinical history and physical examination demonstrating no organic or psychiatric disorders.
    * The electrocardiogram and general blood and urine laboratory tests performed before the study must be within normal ranges. Minor or occasional changes from normal ranges are accepted if, in the investigator's opinion, considering the current state of the art, they are not clinically significant, are not life-threatening for the subjects and do not interfere with the product assessment. These changes and their non-relevance will be justified in writing specifically.
    * Body weight between 50 and 90 kg and body mass index (BMI) between 19-27 kg/m². In case of women, they must weight at least 55 kg to participate. Lower or higher weights and/or BMIs will be accepted if the researchers consider that do not pose a risk to the subjects and do not interfere with the objectives of the study.
    * Recreational use of methylone or other synthetic cathinones, amphetamines and/or ecstasy at least 6 occasions (two in the previous year) without serious adverse reactions.
    * Women who have regular 26-32 day menstrual cycles (maximum 35 days). Participation only in follicular phase of menstrual cycle.
    * Participants who agree to use reliable methods of contraception during the study such as abstinence, intrauterine devices, barrier methods with or without spermicide, or who have a vasectomized partner.

    Exclusion Criteria:

    * Present history of a substance use disorder according to Diagnostic and Statistical Manual for Mental Disorders (DSM-V), except for nicotine. Past history of mild substance use disorder (corresponding to substance abuse according to DSM-IV) could be included.
    * Having had any somatic disease or having undergone major surgery in the 3 months prior to inclusion in the trial.
    * Individual psychiatric history or schizophrenia in first-degree relatives.
    * Previous or actual psychiatric disorders, alcoholism, abuse of prescription drugs or illegal substances or regular consumption of psychoactive drugs.
    * Daily consumption of \>40 grams of alcohol and/or \>20 cigarettes.
    * Blood donation 8 weeks before or participation in other clinical trials with drugs in the previous 12 weeks. In the exceptional case of having participated in this study, there is a washout period of 2 months.
    * History of allergy or serious adverse reactions to medications and/or drugs.
    * Pathological history or evidence of a preexisting condition (including gastrointestinal, liver, or kidney disorders) that may alter the absorption, distribution, metabolism or excretion of drugs or symptoms suggestive of drug-induced gastrointestinal irritation.
    * Subjects unable to understand the nature, consequences of the study and the procedures requested to be followed.
    * Subjects with positive serology to Hepatitis B, C or HIV.
    * Having taken medication regularly in the month prior to the study sessions, excepting vitamins, herbal remedies or dietary supplements that, according to the researchers, do not pose a risk to the subjects and do not interfere in the objectives of the study. Single doses of symptomatic medication in the week prior to experimental sessions will be admitted if it is assumed that blood concentrations have been eliminated on the day of the experimental session.
    * Women who are pregnant or breastfeeding, or who use hormonal contraceptives or do not use reliable contraceptive measures during the study (such as abstinence, intrauterine devices, barrier methods or with a vasectomized partner).
    * Women with amenorrhea or severe premenstrual syndrome.

    Primary Outcomes

    • Non-invasive systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) were repeatedly recorded at baseline (45 and 30 min) prior to administration, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Blood pressure measured in mmHg.

    Secondary Outcomes

    • Heart rate was repeatedly recorded at baseline (45 and 30 min) prior to administration, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Heart rate measured in beats per minute (bpm).

    • Oral temperature was repeatedly recorded at baseline (45 and 30 min) prior to administration, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Oral temperature measured in Celsius degrees (ºC).

    • Pupil diameter was repeatedly recorded at baseline (45 and 30 min) prior to administration, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Pupil diameter measured in millimeters (mm).

    • Maddox wing is a device that measures the balance of extraocular muscles and quantifies exophoria as an indicator of extraocular muscle relaxation. From 22 (exophoria) to 15 (esophoria). It is measured at baseline (45 and 30 min) prior to administration, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h.

    • Intensity of effects will be measured using a visual analog scale (0-100 mm) at baseline (h) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Higher mm means more intensity of effects.

    • High will be measured using a visual analog scale (0-100 mm) at baseline and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Higher mm means more high feeling.

    • Stimulation will be measured using a visual analog scale (0-100 mm) at baseline and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Higher mm means more stimulation.

    • Liking will be measured using a visual analog scale (0-100 mm) at baseline and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h after administration. Higher mm means more liking.

    • Global drug effects will be measured using the short form (49 items) of the Addiction Research Center Inventory (ARCI). This is a true/false response questionnaire with 49 items. The global results include five subscales (sedation, euphoria, dysphoria, intellectual efficiency and amphetamine-like effects. It is administered at baseline and 1, 2, 3, 4, 6, 8, and 10 h after administration. Scores range usually from a total of 12 to 57 points. More points mean more effects.

    • Global drug effects will be measured using the Evaluation of the Subjective Effects of Substances with Abuse Potential questionnaire (VESSPA-SSE). This questionnaire consists of 36 items (0-4 score) that evaluate subjective effects related to stimulants such as MDMA. VESSPA includes six subscales (sedation, psychosomatic anxiety, changes in perception, pleasure and sociability, activity and energy, and psychotic symptoms). Scores of each subscale ranges from 0 to 24 (maximal effects) It is administered at baseline and 1, 2, 3, 4, 6, 8, and 10 h after administration.

    • Calculation of maximum concentration of methylone (ng/mL) in samples collected from 15 min prior to administration (time 0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours.

    • Calculation of maximum concentration of MDMA (ng/mL) in samples collected from 15 min prior to administration (time 0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours.

    • Time (h) to reach maximum concentration of methylone in plasma after administration.

    • Time (h) to reach maximum concentration of MDMA in plasma after administration.

    • Calculation of AUC with samples collected from 15 min prior (time 0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours after methylone administration.

    • Calculation of AUC with samples collected from 15 min prior (time 0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours after MDMA administration.

    • Calculation of maximum concentration (ng/mL) of methylone in oral fluid (saliva) samples collected with a Salivette device at the same time points as serum. Oral fluid is collected 15 min before administration (time 0), at to 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours.

    • Calculation of maximum concentration (ng/mL) of MDMA in oral fluid (saliva) samples collected with a Salivette device at the same time points as serum. Oral fluid is collected 15 min before administration (time 0), at to 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours.

    • Time (h) to reach maximum concentration of methylone in oral fluid after administration.

    • Time (h) to reach maximum concentration of MDMA in oral fluid after administration.

    • Calculation of AUC with oral fluid samples collected from 15 min prior to methylone administration (time 0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours.

    • Calculation of AUC with oral fluid samples collected from 15 min prior to MDMA administration (time 0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours.

    • Urine was collected 15 minutes before administration (time 0) and then between 0-4 h, 4-8 h, 8-12 h, and 12-24 h after methylone administration.

    • Urine was collected 15 minutes before administration (time 0) and then between 0-4 h, 4-8 h, 8-12 h, and 12-24 h after MDMA administration.

    • Concentration of methylone in ng/patch. Samples were collected with dermal patches (5 x 5 cm areas) applied to the back and removed at different intervals such as: 0-2 h, 0-4 h, 0-6 h, 0-8 h, and 0-10 h, 10-12 h.

    • Concentration of MDMA in ng/patch. Samples were collected with dermal patches (5 x 5 cm areas) applied to the back and removed at different intervals such as: 0-2 h, 0-4 h, 0-6 h, 0-8 h, and 0-10 h, 10-12 h.

    • In the pharmacological class identification questionnaire, the participant selects the pharmacological class that better describes the administered drug. This questionnaire is administered 8 h after administration.

    • Test will be performed using specific computer software that assesses simple reaction time to a numeric stimulus. Results are milliseconds (increased simple reaction time is related to worst psychomotor performance) It is measured at baseline (45 and 30 min) prior to administration, and at 1 and 2 h.

    • YMRS (11 items) assessing manic symptoms from 0 to 4 (total score from 0 to 44). It is measured at baseline (30 min) prior to administration, and at 0.5, 1, 4, and 6 h after administration. A higher score indicates a higher severity of mania.

    More Details

    NCT Number: NCT05488171
    Other IDs: HUGTP/METI/FIS/1
    Study URL: https://clinicaltrials.gov/study/NCT05488171
    Last updated: Sep 29, 2023