Abuse Potential and Human Pharmacology of Methylone

Study Overview
=================
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Abuse Potential and Human Pharmacology of Methylone

Conditions
-----------------
Substance Use, Healthy Subjects

Intervention / Treatment
-----------------
* Drug: Methylone
* Drug: 3,4-methylenedioxymethamphetamine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylone<br>Methylone (3,4-methylenedioxy-N-methylcathinone) 200 mg, single dose, oral administration | Drug: Methylone<br>* Single oral dose of 200 mg of methylone.<br>* Other names: MDMC;|
| Active Comparator: 3,4-methylenedioxymethamphetamine (MDMA)<br>MDMA (3,4-methylenedioxymethamphetamine) 100 mg, single dose, oral administration | Drug: 3,4-methylenedioxymethamphetamine<br>* Single oral dose of 100 mg of MDMA.<br>* Other names: Ecstasy;|
| Placebo Comparator: Maltodextrin<br>Placebo, single dose, oral administration | Drug: Placebo<br>* Single oral dose of placebo.<br>* Other names: Non active treatment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood pressure: Emax (peak/maximum effects) in blood pressure | 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. | Differences from baseline to 24 hours after administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Heart rate: Emax (peak/maximum effects) in Heart rate | 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). | Differences from baseline to 24 hours after administration | 
| Change in Oral temperature: Emax (peak/maximum effects) in Oral temperature | 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). | Differences from baseline to 24 hours after administration | 
| Change in Pupil diameter: Emax (peak/maximum effects) in Pupil diameter | 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). | Differences from baseline to 24 hours after administration | 
| Change in Maddox Wing score (MW): Emax (peak/maximum effects) | 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. | Differences from baseline to 24 hours after administration | 
| Change in Intensity of effects: Emax (peak/maximum effects) in Intensity of effects | 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. | Differences from baseline to 24 hours after administration | 
| Change in High: Emax (peak/maximum effects) in High feeling | 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. | Differences from baseline to 24 hours after administration | 
| Change in Stimulated: Emax (peak/maximum effects) in Stimulated 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. | Differences from baseline to 24 hours after administration | 
| Change in Liking: Emax (peak/maximum effects) in Liking feeling | 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. | Differences from baseline to 24 hours after administration | 
| Change in global drug effects assessed with ARCI: Emax (peak/maximum effects) in global drug effects | 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. | Differences from baseline to 24 hours after administration | 
| Change in global drug effects assessed with VESSPA: Emax (peak/maximum effects) in global drug 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. | Differences from baseline to 24 hours after administration | 
| Maximum plasma concentration (Cmax) of methylone | 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. | From baseline to 24 hours after methylone administration | 
| Maximum plasma concentration (Cmax) of MDMA | 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. | From baseline to 24 hours after MDMA administration | 
| Time to reach maximum plasma concentration (Tmax) of methylone | Time (h) to reach maximum concentration of methylone in plasma after administration. | From baseline to 24 hours after methylone administration | 
| Time to reach maximum plasma concentration (Tmax) of MDMA | Time (h) to reach maximum concentration of MDMA in plasma after administration. | From baseline to 24 hours after MDMA administration | 
| Area under the concentration-time curve (AUC 0-24 h) of methylone in plasma concentrations | 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. | From baseline to 24 hours after methylone administration | 
| Area under the concentration-time curve (AUC 0-24 h) of MDMA in plasma concentrations | 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. | From baseline to 24 hours after MDMA administration | 
| Maximum oral fluid concentration (Cmax) of methylone | 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. | From baseline to 24 hours after methylone administration | 
| Maximum oral fluid concentration (Cmax) of MDMA | 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. | From baseline to 24 hours after MDMA administration | 
| Time to reach maximum oral fluid concentration (Tmax) of methylone | Time (h) to reach maximum concentration of methylone in oral fluid after administration. | From baseline to 24 hours after methylone administration | 
| Time to reach maximum oral fluid concentration (Tmax) of MDMA | Time (h) to reach maximum concentration of MDMA in oral fluid after administration. | From baseline to 24 hours after MDMA administration | 
| Area under the concentration-time curve (AUC 0-24h) of methylone oral fluid concentrations | 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. | From baseline to 24 hours after methylone administration | 
| Area under the concentration-time curve (AUC 0-24h) of MDMA oral fluid concentrations | 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. | From baseline to 24 hours after MDMA administration | 
| Total amount methylone excreted in 24 h urine samples. | 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. | From baseline to 24 hours after methylone administration | 
| Total amount MDMA excreted in 24 h urine samples. | 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. | From baseline to 24 hours after MDMA administration | 
| Total concentration of methylone present in sweat | 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. | From baseline to 12 hours after methylone administration | 
| Total concentration of MDMA present in sweat | 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. | From baseline to 12 hours after MDMA administration | 
| Pharmacological class identification | 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. | Only administered 8 hours after administration | 
| Change in psychomotor vigilance task (PVT): Emax (peak/maximum effects) | 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. | Differences from baseline to 2 hours after administration | 
| Psychiatric evaluation using Young Mania Rating Scale (YMRS) | 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. | Differences from baseline to 6 hours after administration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
methylone, pharmacokinetics, acute effects, MDMA, abuse liability, human pharmacology