Table 1.

Clinical trials involving ECS modulators and CVDs or cardiovascular risk factors.

Trial	ECS Modulator	Readouts	Findings	Phase
“A Double-Blind, Randomised, Placebo-Controlled, Cross-Over Study on the Pharmacokinetics and Effects of Cannabis”-NCT00225407, 2005.	Smoking cannabis cigarettes (different Δ9-THC strengths).	Primary: Serum Δ9-THC concentration over time; physical parameters (HR, BP); psychomotor tests (e.g., continuous attention); event related potentials. Secondary: Self-reporting questionnaires.	HR and intoxication were positively linearly associated with increasing Δ9-THC doses (29.3, 49.1, 69.4 mg).	Phase 1.
“Laboratory Study of the Influence of Oral Cannabidiol on the Subjective, Reinforcing and Cardiovascular Effects of Smoked Marijuana”-NCT01844687, 2013.	Active cannabis with 0, 200, 400 or 800 mg CBD; inactive cannabis (containing 0.56% Δ9-THC) with 0, 200, 400 or 800 mg CBD.	Primary: “Feeling high”mood scale-subscale. Secondary: rating form assessing, experience, strength, additional puffs taken, HR, plasma concentration of CBD.	Oral CBD pre-treatment does not alter the subjective, reinforcing, or cardiovascular effects of smoked cannabis. Active cannabis produced significant increases in ratings of “High” and “Good Effect” as well as assessments of the cannabis cigarette (e.g., “Strength”, “Liking”, “Desire to take again”) and HR.	Phase 2.
“A single dose of cannabidiol reduces BP in healthy volunteers in a randomized crossover study”. University of Nottingham (UK) study reference code: E18102012, c.2017.	CBD (600 mg).	Cardiovascular parameters: Systolic, diastolic and mean arterial BP, HR, stroke volume, CO, ejection time, total peripheral resistance, and forearm blood flow.	Acute administration of CBD reduces resting BP.	Phase 1.
“The Effects of Cannabinoids on Vascular and Cognitive Function in Young and Old Healthy Adults”-NCT03295903, 2018.	CBD and TurboCBD™.	Primary: Circulating CBD and nitric oxide markers and vascular function. Secondary: Height, weight, body mass index, systolic and diastolic BP, HR, respiration, questionnaires (medical history, gastrointestinal distress, anxiety), cognitive and exercise performance evaluations.	TurboCBD™ had higher bioavailability than CBD and at 90 mg was associated with increased cerebral perfusion and slight reduction in BP.	Phase 1.
“Hemp Seed Protein Consumption for Hypertension“-NCT03508895, 2018.	Hemp seed protein.	Primary: Change in 24 h ambulatory BP. Secondary: Change in BP, pulse wave velocity, augmentation index, body weight, waist circumference, hip circumference, body composition, total serum cholesterol, HDL/LDL cholesterol, serum triglycerides, serum glucose, serum creatinine, plasma insulin concentrations, insulin homeostasis modelling assessment, renal panel.	No data to date.	Phase 2.
CANNASTROKE “Prevalence of Strokes Secondary to a Reversible Cerebral Vasoconstriction Attributable to Cannabis Consumption in Young Subjects (≤45 Years) Hospitalized for an Ischaemic Stroke”-NCT03379857, 2017.	Cannabis.	Primary: Evaluation of cannabis use, reversible vasoconstriction on medical imaging of intracranial arteries.	No data to date. Estimated primary completion date: January 2025.	Not applicable (behavioural study).
“Atherosclerotic Plaque Texture-Experimental and Clinical Study on the Diagnostic and Therapeutic Strategies of Atherosclerotic Plaque Vulnerability”-NCT00636766, 2005.	Rimonabant combined with exercise.	Primary: Ultrasound and immuno-histochemical parameters of plaque stability and novel cardiovascular risk factors. Secondary: Long-term cardiovascular outcomes.	Rimonabant and exercise induced plaque regression and promoted plaque stability. A combination of the two interventions failed to show additive or synergistic benefits.	Phase 3.
RIO-Europe “A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Fixed-Dose, Multicenter Study of Weight-Reducing Effect and Safety of SR141716 in Obese Patients With or Without Comorbidities”-NCT00386061, 2001.	Rimonabant (5/20 mg daily), reduced caloric intake and exercise promotion.	Primary: Change in body weight, waist circumference, and BP from baseline to 1 year. Secondary: Lipid profile, HDL cholesterol and triglycerides; patients (%) with improvement of glucose tolerance, patients (%) with NCEP-ATPIII metabolic syndrome.	Rimonabant produced weight loss and significant improvements in multiple cardiometabolic risk factors.	Phase 3.
STRADIVARIUS “Strategy To Reduce Atherosclerosis Development InVolving Administration of Rimonabant-the Intravascular Ultrasound Study”-NCT00124332, 2005.	Rimonabant (20 mg, daily for 18–20 months).	Primary: Change from baseline in percent atheroma volume. Secondary: Change from baseline in normalized TAV.	After 18 months of treatment, no effect of rimonabant on the primary efficacy parameter. A statistically significant favourable effect on the secondary end point was observed.	Phase 3.
ADAGIO-Lipids Trial “Effect of Rimonabant on the High-Triglyceride/ Low–HDL-Cholesterol Dyslipidemia, Intra-abdominal Adiposity, and Liver Fat”-NCT00239967, 2005.	Rimonabant (20 mg daily for 12 months).	Measurements of LDL particle size, HDL quantity, quality and subfractions, and apo B/apo A1 ratio; assessments of visceral and liver fat (by a computed tomography sub-study).	Rimonabant significantly improved multiple cardiometabolic risk markers and induced significant reductions in both intra-abdominal and liver fat.	Phase 3.
AUDITOR “Atherosclerosis Underlying Development Assessed by Intima-Media Thickness in Patients on Rimonabant”-NCT00228176, 2005.	Rimonabant (20 mg daily for 30 months).	Primary: Absolute change from baseline in averaged per patient CIMT. Secondary: First occurrence of any component of stroke/MI/cardiovascular death. First occurrence of any component of stroke/MI/cardiovascular death/hospitalization for revascularization procedure, unstable angina, transient ischaemic attack.	No difference in atherosclerosis progression between patients receiving rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in CIMT).	Phase 3.
CRESCENDO “Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints and Outcomes”-NCT00263042, 2005.	Rimonabant (20 mg daily up to 13.4 months).	Primary: First occurrence of any of myocardial infarction, stroke or cardiovascular death. Secondary: First occurrence of any of myocardial infarction, stroke, cardiovascular death, cardiovascular hospitalization and all-cause mortality.	No evidence for the efficacy of prevention of adverse cardiovascular outcomes by rimonabant. Rimonabant was associated with serious side-effects (e.g., neuropsychiatric, gastrointestinal) and the trial was discontinued.	Phase 3.
PRIMARIA “Early Detection of Atherosclerosis in the Primary Care Setting: a Randomized Trial to Assess the Efficacy of a Novel Strategy in the Primary Prevention of Cardiovascular Diseases”-NCT00734123, 2008.	Rimonabant.	Primary: CIMT progression/regression. Secondary: Cardiac and cerebrovascular events.	No data to date.	Phase 4.
CAPITAL-AC “Cannabidiol in Patients With Heart Failure in AHA/ACC Stages A-C”-NCT03634189, 2021.	CBD.	Primary: Number of participants with treatment-related serious adverse events and events of interest as assessed by MedDRA v5.1.	No data to date. Estimated study completion date: December 2021.	Phase 1.
“Study to Evaluate the Efficacy and Safety of CardiolRx™ in Patients With COVID-19 and Cardiovascular Disease or Risk Factors A Double-blind, Placebo-controlled Trial”-NCT04615949, 2021.	CBD, pharmaceutically produced with <5 ppm THC.	Primary: All-cause mortality, ICU admission, ventilator support, cardiovascular complications.	No data to date. Estimated study completion date: September 2021.	Phase 2, 3.

Δ⁹-THC, delta-9-tetrahydrocannabinol; HR, heart rate; BP, blood pressure; CBD, cannabidiol; CO, cardiac output; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TAV, total atheroma volume; CIMT, carotid intima-media thickness; MI, myocardial infarction; ICU, intensive care unit.