A study to test the safety and effects of a new CB1 antagonist ANEB-001 in healthy occasional cannabis users

INTERVENTION: The study will consist of two parts, called “Phase 1” and “Phase II”. In phase I, 20 subjects will be randomized to receive single doses of 50 mg ANEB‐001, or 100 mg ANEB‐001, or placebo each (60 subjects in total in phase I). In phase II, up to 6 extension cohorts of 15 subjects each (10 active and 5 placebo each) may be conducted following the completion of the initial phase based on emerging PK, PD, safety and tolerability data. The subject in the extension cohorts may receive single doses ranging from 10 mg to 150 mg of ANEB‐001 or matching placebo, based on emerging data. Each subject in both phase I and phase II will receive a single dose of 10.5 mg THC (NB: no placebo THC in the study) together with the single dose of ANEB‐001 or placebo ANEB‐001. The duration of treatment and follow‐up is identical for phase I and phase II. The total duration of the study for each subject will be up to 56 days divided as follows: Screening: Up to 42 days before dosing; In Clinic period: Days ‐1 to 2; Follow‐up visit: 7 to 14 days after dosing Subjects will be admitted to the study unit on Day ‐1. The study drugs will be administered in the morning of day 1. Subjects will be discharged approximately 24 hours after study drug administration CONDITION: Effects of ANEB‐001 in healthy occasional users of cannabis ; Not Applicable PRIMARY OUTCOME: Measured at pre‐dose to 8 hours post‐dose (unless noted otherwise):; 1. Visual Analogue Scale (VAS) “Feeling High” according to modified Bowdle psychedelic scale (mm); 2. VAS “Alertness” according to Bond and Lader (mm); 3. Body sway: antero‐posterior sway (mm); 4. Heart rate (bpm) measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose INCLUSION CRITERIA: 1. Signed informed consent prior to any study‐mandated procedure 2. Healthy subjects, 18 to 45 years of age, inclusive at screening 3. Body mass index (BMI) between 18 and 30 kg/m², inclusive at screening, and with a minimum weight of 50kg 4. All males must practice effective contraception during the study and be willing and able to continue contraception for at least 90 days after their last dose of study treatment 5. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions 6. Occasional cannabis users SECONDARY OUTCOME: Measured at pre‐dose to 8 hours post‐dose (unless noted otherwise):; 1. VAS Bond and Lader: mood (mm), calmness (mm).; 2. VAS Bowdle Internal perception, External perception; 3. State‐Trait Anxiety Inventory (STAI) State anxiety score measured pre‐dose to 4 hours post‐dose; 4. Saccadic eye movements: saccadic reaction time (second), saccadic peak velocity (degrees/second), and saccadic inaccuracy (%);; 5. Smooth pursuit eye movements: percentage of time the eyes of the subjects are in smooth pursuit of the target (%);; 6. Adaptive tracking: average performance (%);; 7. Pupillometry (mm) ; 8. N‐Back, Average reaction time for zero, one and two‐back (ms), (nr correct – nr incorrect)/total for zero, one and two‐back; 9. PK parameters of ANEB‐001, THC and 11‐OH‐THC by non‐compartmental analysis of the plasma concentration‐time data measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose: ; 9.1 AUCinf, AUClast, CL/F, Cmax, t1/2, tlag, tmax, Vz/F; 9.2 Dose‐normalized PK parameters: AUCinf, AUClast, Cmax; 10. Treatment‐emergent (serious) adverse events ((S)AEs) throughout the study at every study visit ; 11. Concomitant medication throughout the study at every study visit ; 12. Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg)) as per assessment schedule measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose; 13. Clinical laboratory tests (Hematology, blood chemistry and urinalysis) measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose; 14. ECG parameters (Heart Rate (HR) (bpm), PR, QRS, QT, QTcB, QTcF) measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose; 15. VAS Nausea; 16. Suicidality as assessed by the Columbia Suicide Severity Rating Scale (C‐SSRS) measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose; 17. Depressive symptoms as assessed by Beck Depression Inventory‐II measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose; 18. Dissociative symptoms as assessed by Clinician Administered Dissociative States Scale (CADSS) measured pre‐dose to 24 hours post‐dose, and at follow up 7‐15 days post‐dose