Terminated by the sponsor in the context of COVID-19 pandemia

Background:

Tetrahydrocannabinol (THC) is a partial CB1/CB2 agonist and causes its pharmacological effects by binding to cannabinoid receptors. CB1 receptors are predominantly located in the brain (highest densities at hippocampus, cerebellum and the striatum) and at low levels in the brainstem. CB2 receptors are predominantly in the spleen and in hematopoietic cells. THC is highly lipophilic and is readily absorbed and distributed to the brain and other organs.

Most of the neuropsychological studies carried out so far show that the mainly affected neurocognitive functions in cannabis users are: memory, attention, psychomotor capacity, speed of information processing and alterations of executive functions (resistance to interference, planning capacity, decision-making, verbal fluency and working memory). These effects are dose-dependent.

Hypothesis:

Functional CB1 receptor activation by the THC contained in the cannabis flos will induce dose-dependent effects on EEG, physiological functions and behavior:

1. EEG alterations.
2. Increase in cannabis subjective effects.
3. Increase in heart rate.
4. Increase in psychopathology scale Psychotomimetic State Inventory (PSI) score.
5. Increase in plasma cortisol concentrations.

Objectives:

Main pharmacodynamic objective: To assess the effects of Cannabis flos on electroencephalography (EEG) in healthy recreational cannabis users.

Secondary pharmacodynamic objectives: (i) To assess the effects of Cannabis flos on: cannabis subjective effects, heart rate and psychopathology scale; (ii) To establish the pharmacokinetic/pharmacodynamic relationships between THC plasma concentrations and pharmacodynamic endpoints.

Safety and tolerability objectives: To assess the safety and tolerability of THC in these subjects.

Methods:

Phase I, prospective, monocentric, double-blind, randomized, placebo-controlled, parallel group study to assess the THC effects on EEG neural oscillations in 16 healthy subjects with recreational cannabis use.

Subjects will be randomly assigned in a 2:1 ratio to either Arm A (Cannabis) or Arm B (Cannabis placebo). The subjects, Investigators and designees involved in the conduct of the study will be blinded to the identity of the treatment administered during the study.

In the active group (Arm A) subjects will be administered four single doses of 20 mg THC over 3 days, equivalent to 285.7 μg/kg. This dose is considered to be sufficient for eliciting the psychoactive effects of THC (> 5 ng/mL in plasma) and modify EEG, avoiding subjects to be too much behaviorally impaired.

THC will be administered in the form of medical cannabis (Bedrocan®) inhaled by intrapulmonary route. It is featured in flos form (Cannabis sativa dried female flower) containing THC 22% and cannabidiol (CBD) <1%. A vaporization system (Mighty® Medic device) will be used for cannabis administration. Through this system, the final inhalation of THC is comparable to that of smoking cannabis while reducing the inhalation of toxic and irritating substances generated in the combustion of herbs.

Inclusion Criteria:

• Healthy male or female subjects.
• Negative urine pregnancy test and effective contraception method for female of child-bearing potential (see footnote at the end of subheading 5).
• Age ≥ 18 and ≤ 55 years.
• Weight ≥ 50 kg and ≤ 100 kg.
• Body mass index (BMI) ≥ 18 and ≤ 30.
• Recreational cannabis use with a cannabis use history ≥ 6 months and a cannabis consumption in the last month ≥ 1 day/month and ≤ 2 days/week.
• Last cannabis consumption ≥ 1 week before Day 1.
• Negative urine drug test but for cannabis.
• Consistent drug hair test (performed during screening) with drug use medical history.
• Able to read Spanish and adhere to study requirements.
• Not under any administrative or legal supervision.
• Signed informed consent prior to any study-mandated procedure.

Exclusion Criteria:

• Pregnant or nursing female.
• Cannabis-naive subjects.
• Life-time cannabis use disorder (CUD) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM).
• Recreational use of opioids, cocaine, psychostimulants within the last month.
• Life-time other substance use disorders (SUD) according to the DSM-5 criteria using PRISM, except for mild alcohol use disorder and/or mild or moderate nicotine use disorder.
• Life-time history of bipolar disorders, psychosis or suicidal attempts assessed by the Dual Diagnosis Screening Instrument (DDSI).
• Past-12 months history of anxiety or depression assessed by the DDSI.
• Life-time clinically significant cardiovascular, renal, pulmonary, hepatic, onco-hematological, endocrine, gastrointestinal or neurological disease.
• Any other diseases or conditions that in the judgment of the investigator would interfere with the subject's ability to comply with study procedures or requirements and/or study results interpretation.
• Any clinically significant findings in physical examination including vital signs, EEG and safety laboratory parameters.
• Any prescription or over the counter drug (except occasional use of paracetamol) in the last 2 weeks before Day 1 of each period.
• Patient included in a clinical study in the last three months.

The subjects, Investigators and designees involved in the conduct of the study will be blinded to the identity of the treatment administered during the study.

The following precautions will be taken to ensure the integrity of the study blinding during the trial:

• The monodose capsules containing the treatment conditions will be prepared by an unblinded technician who will not be involved in any study assessment. The unblinded technician will also maintain records for drug accountability.
• Treatment will not be unblinded for an individual subject except for a medical emergency.