Table 2. CBD adverse effects in clinical studies.

Study Characteristic	Patients' Characteristic		Oral CBD Dose		Simultaneous Drug Administration		Reported Adverse Effects (AEs)		Refs.
Neurological studies
Parental report: online survey	Age 2-16; 18 patients with Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, or idiopathic epilepsy		0.5–28.6 mg/kg/day (2 weeks–12 months)		Not reported		Moderate (defined as: sufficiently discomforting so as to limit or interfere with daily activities and may require interventional treatment): drowsiness (37%), fatigue (16%)		Porter and Jacobson, 2013 [68]
Parental report: online survey	Age 3-10; 117 patients with Dravet syndrome, Lennox-Gastaut syndrome, or infantile spasms		Median of 4.3 mg/kg/day (6.8 months)		Clobazam, other not-specified antiepileptics		AEs in 59% patients; Moderate: increased appetite, weight gain, drowsiness		Hussain et al., 2015 [67]
Open-label study, expanded-access trial in 11 independent epilepsy centers	Age 1-30; Patients with treatment-resistant epilepsy; 162 patients in safety analysis group (33 with Dravet syndrome, 31 with Lennox-Gastaut syndrome)		2–5 mg/kg/day increased until intolerance or to a maximum of 25–50 mg/kg/day (12 weeks)		Clobazam, valproate		AEs in 79% safety group patients (128/162); Moderate: somnolence, fatigue, lethargy, sedation, decreased or changes in appetite, diarrhea, transaminases increase, changes of antiepileptics serum concentration; Severe: status epilepticus, convulsions, diarrhea, weight loss, thrombocytopenia, hyperammonaemia, hepatotoxicity		Devinsky et al., 2016 [70]
Retrospective study with no control group	Age 1-18; 74 patients with treatment-resistant epilepsy		1–20 mg/kg/day; 81% patients (60/74) with < 10 mg/kg, 19% (14/74) with >10 mg/kg (> 3 months, average 6 months)		Not reported		AEs reported in 47% patients (34/74); Moderate: seizure aggravation (5 patients stopped CBD treatment due to seizure aggravation), somnolence, fatigue, gastrointestinal disturbances, irritability		Tzadok et al., 2016 [69]
Double-blind, randomized, placebo-controlled trial	Age 2-18; 120 patients with Dravet syndrome		20 mg/kg/day (14 weeks)		Median of 3 antiepileptics (e.g., clobazam, valproate)		AEs in 93% patients; Moderate: diarrhea, loss of appetite, lethargy, fatigue, pyrexia, convulsion, elevated aminotransferase levels, somnolence; Severe (10 patients): elevated levels of liver aminotransferase enzymes (n=3), status epilepticus (n=3)		Devinsky et al., 2017 [71]
Double-blind, randomized, placebo-controlled trial	Age 4-10; 34 patients with Dravet syndrome		5, 10, or 20 mg/kg/day (4-week baseline, 3-week treatment, 10-day taper, and 4-week follow-up)		Clobazam, valproate, levetiracetam, topiramate, stiripentol		Treatment-emergent AEs (TEAEs) reported in 80% patients with 5 mg/kg (8/10), 63% patients with 10 mg/kg (6/8), 78% patients with 20 mg/kg (7/9), 86% patients with placebo (6/7); Moderate: pyrexia, sedation, somnolence, appetite loss, vomiting, ataxia, abnormal behavior, rash; Severe: pyrexia, maculopapular rash, elevated transaminases		Devinsky et al., 2018 [74]
Double-blind, randomized, placebo-controlled trial	Age 2-55; 225 patients with Lennox-Gastaut syndrome		10 or 20/mg/kg/day (28 days)		Not-specified antiepileptics		AEs in 84% patients with 10 mg/kg (56/67), in 94% patients with 20 mg/kg (77/82); Moderate: somnolence, decreased appetite, diarrhea, upper respiratory tract infection, pyrexia, vomiting; Severe: elevated aspartate aminotransferase (AST) concentration, elevated alanine aminotransferase (ALT) concentration, elevated γ-glutamyltransferase concentration, somnolence, increased seizures during weaning, nonconvulsive status epilepticus, lethargy, constipation, worsening chronic cholecystitis		Devinsky et al., 2018 [75]
Study Characteristic		Patients' Characteristic		Oral CBD Dose		Simultaneous Drug Administration		Reported Adverse Effects (AEs)	Refs.
Neurological studies
Double-blind, randomized, placebo-controlled trial		Age 2-55; 171 patients with Lennox-Gastaut syndrome		20/mg/kg/day (14 weeks)		Clobazam, valproate, lamotrigine, levetiracetam, rufinamide		AEs in 62% patients (53/86); Moderate: diarrhea, somnolence, pyrexia, decreased appetite, vomiting; Severe: increased ALT concentration, increased AST concentrations, increased γ-glutamyltransferase concentrations	Thiele et al., 2018 [65]
Ongoing expanded‐access program (EAP)		Age 0.4-62 (average 13); 607 patients with treatment-resistant epilepsy		2-10 mg/kg/day increased to a maximum of 25-50 mg/kg/day; median duration 48 weeks		Up to 10, including clobazam, lamotrigine, topiramate, rufinamide, valproate, levetiracetam, stiripentol, felbamate		AEs in 88% patients; Moderate: diarrhea, somnolence, convulsions; Severe (33%): convulsions, status epilepticus, liver abnormalities (10%)	Szaflarski et al., 2018 [66]
Psychiatric studies and psychiatric AEs
Double-blind, randomized CBD versus amisulpride trial		Age 18-50; 42 patients with acute paranoid schizophrenia or schizophreniform psychosis		200 mg/day increased to a maximum of 800 mg/day (28 days)		Lorazepam		Fewer motor disturbances, weight gain, and sexual dysfunction than amisulpride	Leweke et al., 2012 [38]
Meta-analysis of studies & reviews on CBD efficacy & safety in schizophrenia		57 patients with schizophrenia		300–600 mg		Not reported		Does not decrease anxiety; Frequent AEs (not reported)	Guinguis et al., 2017 [62]
Double-blind, randomized, placebo-controlled trial		Age 18-50; 32 patients with persecutory ideation and anxiety		600 mg		Not reported		AEs in 31% patients (5/16); Tiredness/sedation (n=5), lightheaded/dizziness (n=2), nausea (n=2), abdominal discomfort (n=1), increased appetite/hunger (n=2); A strong trend toward increased anxiety was documented; no effect on persecution ideation	Hundal et al., 2018 [39]
Double-blind, randomized, placebo-controlled trial		Age 18-65; 88 patients with no treatment-resistant schizophrenia or related psychotic disorder		1,000 mg/day (43±3 days)		Not-specified antipsychotics		AEs in 35% patients (15/43) (similar as placebo); Moderate: diarrhea (n=4; placebo, n=2), nausea (n=3), headache (n=2, placebo, n=2)	Mc Guire et al., 2018 [35]