Table 1.

A visual summary of the characteristics from included studies from the systematic review.

Reference	Study Design/Sample	Treatment	Investigational Product Formulation	Concomitant Therapy	Safety Assessment	Adverse Effects	Serious Adverse Effects
Appiah-Kusi et al., 2020 [10]	RCT, phase I, double-blind, between-groups, placebo-controlled. 33 clinical high-risk psychosis volunteers (Age 23–29 y) 16 CBD; 17 placebo 25 healthy volunteers (no use of intervention drug) (Age 23–29 y)	600 mg/day oral CBD for 1 week.	CBD capsules (STI Pharmaceuticals, UK).	None	No adverse event scale or questionnaire was applied	None	None
Ben-Menachem et al., 2020 [11]	RCT, phase II, two-arm, parallel-group, double-blind, placebo-controlled. 34 patients with epilepsy receiving Stiripentol (STP) or Valproate (VPA) and no more than 2 other AEDs (16–55 y). STP arm (n = 14): 12 CBD 2 placebo VPA arm (n = 20): 16 CBD 4 placebo	CBD 20 mg/kg/d administered as two equal doses twice a day for 2 weeks.	Epidiolex® 100 mg/mL (GW Pharma, Cambridge, UK).	Carbamazepine Clobazam Clonazepam Ethosuximide Lacosamide Lamotrigine Levetiracetam Lorazepam Oxcarbazepine Rufinamide Stiripentol Topiramate VPA sodium Zonisamide	Laboratory parameters (liver enzymes) Drug abuse liability (monitored if CBD was overused or went missing)	STP arm: 8 CBD patients experienced mild AE (mostly diarrhea and fatigue). 2 CBD patients experienced ALT and AST increases (solved during the trial) VPA arm: 14 CBD patients experienced mil AE (mostly diarrhea) No AE in the placebo group.	STP arm: 1 generalized rash led to discontinuation. Rash solved after both CBD and STP discontinued. VPA arm: 1 hypertransaminasemia led to discontinuation. SAE solved by day 40.
Efron et al., 2020 [12]	RCT, phase I/II double-blind, parallel-group, placebo-controlled. 8 participants diagnosed with Intellectual Disability (8–16 y). 3 CBD 5 placebo	CBD was up titrated over 9 days from 5 mg/kg/day to 20 mg/kg/d in two divided doses, with a maximum dose of 500 mg twice/d for 8 weeks.	100 mg/mL CBD oral solution. 98% CBD in grapeseed oil (Tilray, Nanaimo, BC, Canada).	Clonidine Fluoxetine Guanfacine Melatonin Methylphenidate Risperidone Sodium Valproate	Safety: Blood collection (liver enzymes) Monitoring of Side Effects Scale (MOSES).	CBD: Eyes rolled up (1), tics (1), ear ringing (1), drooling (1), abdominal pain (1), decreased appetite (1), increased appetite (1), constipation (1), decreased wight (1), increased weight (1), restlessness (1), jitter (1), acne (1), urination incontinence (1), sadness (1), drowsiness (1), excessive sleep (1), insomnia (1). Placebo: Headache (1), nose congestion (1), increased appetite (1), increased weight (3), sadness (1), insomnia (1).	None
Freeman et al., 2020 [13]	RCT, phase II, double-blind, placebo-controlled, parallel-group. 48 patients in 1st stage plus 34 patients in 2nd stage with DSM-V criteria for a cannabis use disorder (at least moderate severity), expressing a desire to stop using cannabis (16–60 y). 77 participants completed treatment. 1st stage: 23 Placebo 12 CBD 200 mg 12 CBD 400 mg 12 CBD 800 mg 2nd stage: 23 Placebo 24 CBD 400 mg 23 CBD 800 mg	Gelatine capsules containing microcrystalline cellulose filler and CBD (50 mg, 100 mg, or 200 mg) for 4 weeks. 2 capsules twice daily: CBD 200 mg 4 capsules 50 mg CBD 400 mg 4 capsules 100 mg CBD 800 mg 4 capsules 200 mg	Synthetic CBD 99.9% purity (STI Pharmaceuticals, UK; manufactured by Nova Laboratories, UK).	None	Participants were asked about possible adverse events at each assessment from week 1 to week 16. All adverse events were verified with a medical supervisor and an independent trial monitor throughout the trial on an ongoing basis.	CBD 200 mg (12): 42 mild and 4 moderate AE CBD 400 mg (24): 96 mild and 8 moderate CBD 800 mg (23): 78 mild and 8 moderate Placebo (23): 65 mild and 9 moderate	None
Meneses-Gaya et al., 2020 [14]	RCT, double-blind, placebo-controlled. 31 patients with DSM-IV diagnosis of crack-cocaine dependence (>18 y). 14 CBD 17 placebo	CBD 300 mg/d. Two 150 mg capsules/d for 10 days.	CBD 99.9% pure powder (THC-Pharm, Germany/ STI-Pharm, Brentwood, UK) dissolved in corn oil.	Benzodiazepines	UKU Side Effects Rating Scale (UKU-SERS)	Sleepiness: 5 CBD; 3 placebo Nausea: 2 CBD; 1 placebo Headache: 2 CBD; 1 placebo	None
Thiele et al., 2020 [15]	RCT of add-on CBD vs. placebo, Phase III, double-blind, parallel-group. 224 included patients with a clinical diagnosis of Tuberous Sclerosis Complex (1–65 y). 75 CBD25 73 CBD50 76 placebo	CBD 25 mg/kg/day (CBD25) or 50 mg/kg/d (CBD50) for 16 weeks. 4 w for dose escalation (titration period) followed by 12 w of stable dosing (maintenance period).	Epidiolex® 100 mg/mL (GW Pharma, UK).	Clobazam Valproic Acid	Safety was assessed primarily by evaluating adverse events and clinical laboratory parameters.	Most common: Diarrhea: 23 CBD25; 41 CBD50; 19 placebo. Somnolence: 10 CBD25; 19 CBD50; 7 placebo. Decreased appetite: 15 CBD25; 17 CBD50; 9 placebo. Liver transaminase level elevations: 17 CBD25; 30 CBD50	Serum aminotransferase level elevations greater than 3 times the upper limit of the normal range: 9 CBD25 19 CBD50 Rash 2 CBD25 2 CBD50 Seizure 3 CBD25 2 CBD50
VanLandingham et al., 2020 [16]	RCT, phase II, double-blind, placebo-controlled. 20 patients with epilepsy taking Clobazam and no more than 2 other antiepileptic drugs (18–65 y). Seven patients (1 taking placebo and 6 taking CBD) were excluded from the PK analysis	CBD 20 mg/kg/d coadministered with Clobazam. Patients titrated their CBD dose for 10 days (days 2 to 11) to 20 mg/kg/d CBD (twice daily). The titration period was followed by a 21d maintenance dose period (days 12 to 32).	Epidiolex® 100 mg/mL (GW Pharma, UK).	Carbamazepine Clobazam Eslicarbazepine Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Perampanel Phenobarbital Valproic acid	Medical Dictionary for Regulatory Activities (MedDRA)	Diarrhea: 6 CBD 6; placebo 1 Nausea: 3 CBD Vomiting: 3 CBD Dizziness: 2 CBD Sedation: 2 CBD Somnolence: 2 CBD Skin tissue disorders: 6 CBD	Seizure cluster: 1 CBD
Crippa et al., 2021 [17]	RCT, phase, II double-blind, parallel-group, placebo-controlled. 105 patients diagnosed with COVID-19 (18–65 y). The data of 91 patients were included in the final analysis: 49 CBD 42 placebo	CBD 300 mg/d administered as two equal doses twice for 2 weeks.	Oral CBD 150 mg/mL 99.6% purity (PurMed Global, USA).	Dipyrone Paracetamol	Modified UKU Side Effects Scale	Somnolence:38 CBD; 33 placebo Fatigue:38 CBD; 33 placebo Decreased appetite:38 CBD; 32 placebo Lethargy:25 CBD; 15 placebo Weight loss:24 CBD; 22 placebo Nausea:23 CBD; 16 placebo Diarrhea:21 CBD; 20 placebo Increased appetite:17 CBD; 10 placebo Fever:11 CBD; 15 placebo Weight gain:10 CBD; 8 placebo	None
De Almeida et al., 2021 [18]	RCT, phase II/III, double-blind, placebo-controlled, parallel-group. 33 patients with Parkinson’s Disease (>18y). 17 CBD 16 placebo	1st week 1 capsule (CBD 75mg) 2nd week 1 capsule (CBD 150 mg) the 3rd until the 12th w 2 capsules (CBD 150 mg)	CBD 99.6% pure powder form (BSPG Pharm, UK) dissolved in corn oil (capsule).	Antidepressants (SSRI or dual) Clonazepam Melatonin	Participants self-report	CBD: Epigastric pain (1), Nausea (1), headache (1), drowsiness (1), sadness (2), and dizziness (1). Placebo: Headache (1).	None
Leweke et al., 2021 [19]	RTC, phase II, parallel-group, active-controlled, mono-therapeutic, double-blind. 42 patients diagnosed with schizophrenia or schizophreniform psychosis (18–50 y). The data of 39 patients were included in the final analysis: 20 CBD 19 Amisulpride	Both CBD and AMI: Initial dose 200 mg/d and increased stepwise by 200 mg per day to a daily dose of 200 mg four times daily (800 mg/d) with the 1st w. Maintained for another 3 weeks (4w total).	Pharmaceutical grade not stated.	Lorazepam	No adverse event scale or questionnaire was applied	Although side effects have been reported (3 CBD; 5 AMI), they have not been described.	None
Mongeau-Pérusse et al., 2021 [20]	RCT: Phase II, double-blind, parallel-group, placebo-controlled. 78 diagnosed with current cocaine use disorder patients (18–65 y). Phase I: Detoxification (10 days); Phase II: 12-w outpatient follow-up. Completed Phase I: 35 CBD; 27 placebo Completed Phase II: 27 CBD; 23 placebo	CBD 300 mg/mL for 92 days. Days 2 and 3: CBD 400 mg (1.3 mL) and then increased the dose to 800 mg/day (2.7 mL) for the rest of the study.	Synthetic CBD 300 mg/mL (Insys Therapeutics, Phoenix, AZ, USA).	None	Systematic Assessment for Treatment Emergent Events (SAFTEE) tool	Diarrhea: 26 CBD; 1 placebo Nausea: 3 CBD; 3 placebo Abdominal pain: 3 CBD Hypoaesthesia: 2 CBD; 1 placebo Abdominal distension: 2 placebo Insomnia: 2 CBD	Placebo group: 1 Hepatitis
Atieh et al., 2022 [21]	RCT, double-blinded, placebo-controlled (1:1 ratio). 48 patients with Functional dyspepsia with normal gastric emptying (18–70 y) 25 CBD 23 placebo	CBD 20 mg/kg/d administered as two equal doses twice a day for 4 weeks.	Epidiolex® 100 mg/mL (GW Pharma, UK).	Analgesic; antibiotic; anticonvulsant; antiemetic; anti-fungal; alpha-2 adrenergic; anxiolytic; antipsychotic; antispasmodic; anti-histaminic; anti-acid secretory agent; anti-migraine; anti-hypertensive; birth control hormones; birth control IUD; bronchodilator; dopaminergic/noradrenergic; epinephrine pen available; hormones; lipid reducing agent; night sedative; NSAIDs; SSRI; topical/nasal steroids; tricyclic antidepressant.	Laboratory parameters (liver enzymes)	Elevated liver enzymes: 4 CBD; 1 placebo Abdominal distension: 6 CBD; 2 placebo Nausea: 5 CBD; 1 placebo Headache: 3 CBD; 1 placebo Diarrhea: 7 CBD; 1 placebo Dizziness: 2 CBD Fatigue: 2 CBD; 3 placebo Loss of appetite: 2 CBD	None

AE adverse effect; AEDs antiepileptic drugs; AMI amisulpride; CBD cannabidiol; IUD intrauterine device; NSAID non-steroidal anti-inflammatory drug; RCT randomized controlled trial; SAE serious adverse effect; SSRI selective serotonin reuptake inhibitor; STP stiripentol; UKU acronym for the Danish name “Udvalg for Kliniske Undersøgelser”—Task force for clinical investigations; VPA valproate.