Dementia (F0 ICD-10) 1 SR [59] of 1 RCT and 3 additional RCTs were identified [1, 82–85]. Volicer et al. [85] found positive effects on mean weight gain in both groups (dronabinol–placebo group by 3.95 kg, placebo–dronabinol group: by 3.13 kg) with a pronounced effect of dronabinol compared to placebo (p = 0.017) (Table 2). A reduction in negative affect (anger, anxiety and sadness) was detected during the treatment with dronabinol, which persisted during the episode following the treatment with dronabinol (ANOVA: F_{(order × treatment) =} 2.78, df = 1, 143, p = 0,12). No effects were found for caloric intake. Three patients dropped out of the study [adverse effects (n = 1), severe infections (n = 2), myocardial infarction during the placebo phase (n = 1)]. In a multi-centered RCT (Table 3) van den Elsen et al. [82] reported that THC did not reduce neuropsychiatric symptoms compared to placebo (block 1–3: 1.8, 97.5% CI − 2.1 to 5.8; block 4–6: − 2.8, 97.5%CI − 7.4 to 1.8). Psychiatric symptoms, agitated behavior and caregiver burden increased in both study arms during the 12 weeks trial. THC was well tolerated, as assessed by adverse event monitoring, vital signs and mobility. The incidence of adverse events was similar between treatment groups. Four non-related serious adverse events occurred. In a sample of ten patients, Ahmed et al. [1] reported that THC was rapidly absorbed and had dose-linear pharmacokinetics with considerable variation. Pharmacodynamic effects, including adverse events, were minor. Another RCT with cross-over design [84] tested the efficacy and safety of low-dose oral THC (3 × 1–5 mg/day, 3 weeks.) or placebo. Neuropsychiatric symptoms were reduced during both treatment conditions, with no difference between THC and placebo (mean difference NPI_total: 3.2, 95% CI 23.6–10.0). No changes in scores for agitation, quality of life, or activities of daily living were found. The number of patients experiencing mild or moderate adverse events was similar (THC: n = 16, placebo: n = 14; p = 0.36). No effects on vital signs, weight, or episodic memory were observed. In all trials, patients could continue their standard medication. In summary, the studies provide a heterogeneous picture: superior effects (weight gain and reduction in negative affect) of THC (given in addition to standard treatment and compared to placebo) were only found in one out of three trials. Adverse effects occurred in all conditions.

Opioid dependence (F11.20 ICD-10) Severity of withdrawal, retention in treatment or safety were assessed in 2 RCTs (3 reports, 70 patients) [12, 37, 48] (Table 3). The first intervention [12] was dronabinol (titrated to 30 mg/day, 3 weeks) (n = 40) compared to placebo (n = 20). Patients were stabilized with buprenorphine (2 × 4 mg/day) (day 2) and received naltrexone from day 5 onwards. The study revealed a significant initial reduction in the severity of the opioid withdrawal during the initial 8-day detoxification phase for dronabinol (up to 30 mg/day) compared to placebo (p = 0.006). No significant difference was found in retention between the groups (35% retained in either group). The rate of successful induction onto XR-naltrexone did not differ between dronabinol (66%) and placebo (55%) groups (χ² = 1.46, p = 0.23). A high number of AEs (96% vs. 91%) was reported. They were considered to be consistent with symptoms of naltrexone-related protracted withdrawal. Jicha et al. [37] and Lofwall et al. [48] tested the safety of dronabinol with n = 12 adults physically dependent on short-acting opioids. Participants were maintained on oral 30 mg oxycodone. The study showed that a higher dosage of dronabinol (40 mg/day) produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30 mg. Compared to placebo, 20 and 30 mg dronabinol produced significant increases in heart rate beginning 1 h after drug administration which lasted approximately 2 h (p < 0.05). Dronabinol 5 and 10 mg produced placebo-like effects. Altogether, the evidence for the usefulness of dronabinol as adjunct medication in the detoxification of opioid-dependent patients is still very small. Only one study shows a reduction in the severity of the opioid withdrawal in the initial detoxification phase. The number of reported adverse events was high in one study (naltrexone-related protracted withdrawal) while safety concerns were given in the second study for dronabinol at 20 mg and higher given in combination with oral oxycodone.

Cannabis dependence (F12.2 ICD-10) Craving, withdrawal and abstinence from cannabis were assessed in 5 RCTs (319 participants) in patients with cannabis dependence [2, 42, 43, 79, 80]. Trigo et al. [80] (Table 3) added nabiximols or placebo to a manualized motivational enhancement therapy and cognitive behavioral therapy. Rates of adverse events did not differ between treatment arms (F_1,39= 0.205, ns). There was no significant change in abstinence rates at trial end. Cannabis use decreased in either group, without significant differences between treatment conditions (p = 0.179). Nabiximols reduced cannabis craving, but no significant differences between groups were observed on withdrawal scores. No serious adverse events were reported. In a previous multi-centered RCT with cross-over design, Trigo et al. [79] tested the effects of nabiximols on both craving and withdrawal symptoms among n = 9/16 non-treatment seeking cannabis-dependent adults. High fixed doses of nabiximols were well tolerated and, compared to placebo, significantly reduced symptoms of cannabis withdrawal during abstinence, but not craving. Self-titrated doses were lower and showed limited efficacy compared to high fixed doses. Participants reported a significantly lower “high” following nabiximols or placebo as compared to treatment as usual conditions. Nausea, diarrhea and sleep disorders were reported, but no serious AEs. Levin et al. [43] assessed abstinence (= 21 consecutive days), withdrawal, craving, and adverse events. The intervention was dronabinol (self-titrated up to 3 × 20 mg/day), lofexidine (self-titrated up to 3 × 0.6 mg/day) or placebo. In both conditions, patients received cannabis-specific manualized behavioral therapy. The trial found no treatment effect in achieving abstinence. Drop-out rates were high (48% vs. 42%). More AEs were found in the dronabinol group (e.g., dry mouth, intoxication, and hypotension), serious AEs (2 cases) were reported in the placebo lead-out phase. In a previous double-blind RCT, Levin et al. [42] tested dronabinol (2 × 20 mg/day) or placebo in addition to weekly motivational enhancement and relapse prevention therapy. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Both groups reduced cannabis use over time (no differences between groups). Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (p = 0.02). Withdrawal symptoms were significantly lower on dronabinol than placebo (p = 0.02). Dronabinol was well-tolerated. Allsop et al. [2] assessed the effects of nabiximols or placebo combined with standardized psychosocial interventions. Nabiximols significantly reduced the overall severity of cannabis withdrawal relative to placebo (p = 0.01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols patients remained longer in treatment during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18–11.37]; p = 0.02), with a number needed to treat of 2.84 to achieve successful retention in treatment. The frequency (p = 0.59) and severity (p = 0.10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (p = 0.75), cannabis-related problems (p = 0.14), or cannabis dependence (p = 0.89). In sum, existing trials provide a heterogeneous picture of the effectiveness of dronabinol and nabiximols in the treatment of cannabis use disorders. Four studies did not find positive effects regarding abstinence or reduction in cannabis use. Three out of five RCTs showed a significant reduction of withdrawal symptoms. Two out of three trials indicate improved craving and one study indicates improved retention in treatment. Adverse effects were more frequently reported in the intervention group in two of three studies. Future studies should use consistent outcome variables (e.g., assessment of abstinence) and treatments (manualized CBT/relapse prevention) in order to provide comparable findings.

Psychoses/Schizophrenia (F20 ICD-10) Two systematic reviews [45, 90] of 6 RCTs [13, 15, 46, 55, 74, 81] and two new RCTs [16, 51] were found (n = 887 participants). In the studies of Leweke and colleagues individuals with psychosis received CBD (800 mg/day, 4 weeks) [46] or CBD (600 mg/day, 2 weeks) [81]. The comparisons were amisulpride (max 800 mg/day) and placebo, respectively. Primary outcomes were psychiatric symptoms [66] and positive and negative symptoms [39]. Both studies found significant improvements vs. baseline on days 14 and 28 for CBD and amisulpride; no difference was found between groups. The authors reported side effects for all medications, but the side-effect profile (extrapyramidal symptoms, weight gain, prolactin values) was considered superior for CBD vs. amisulpride [46]. McGuire et al. [51] conducted a double-blind parallel-group trial where patients with chronic schizophrenia received CBD (1000 mg/day; n = 43) or placebo (n = 45) add-on to the existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale [39], the Global Assessment of Functioning scale (GAF) [40], Brief Assessment of Cognition in Schizophrenia (BACS) [41] and the improvement and severity scales of the clinical global impression scale [17] (CGI-I and CGI-S). After 6 weeks of treatment, compared to the placebo group, the CBD group had lower levels of positive symptoms (PANSS: treatment difference = − 1.4, 95% CI = − 2.5, − 0.2) and were more likely to have been rated as improved (CGI-I: treatment difference = − 0.5, 95% CI = − 0.8, − 0.1) and as not severely unwell (CGI-S: treatment difference = − 0.3, 95% CI = − 0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements which fell short of statistical significance in cognitive performance (BACS: treatment difference = 1.31, 95% CI = − 0.10, 2.72) and in overall functioning (GAF: treatment difference = 3.0, 95% CI = − 0.4, 6.4). CBD was well tolerated, while rates of adverse events were similar between the CBD and placebo groups. Boggs et al. [16] conducted a 6-week parallel-group RCT. The intervention was a fixed-dose study of oral CBD (600 mg/day) or placebo augmentation in n = 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. This study compared the cognitive, symptomatic, and side effects of CBD vs. placebo in a clinical trial. No main effect of time or drug on MATRICS Consensus Cognitive Battery [10], but a significant drug × time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo-treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS total scores over time (p < 0.0001), but there was no significant drug × time interaction (p = 0.18). Side effects were similar between CBD and placebo, with exception being sedation, which was more prevalent in the CBD group. Overall, CBD was well tolerated with no worsening of mood, suicidality or movement side effects. Leweke et al. [45] (LoE: 2; ROBIS: high) included 3 further published double-blind RCTs (of unclear risk of bias). The interventions were Rimonabant [15, 55] and drinabant (AVE1625) [74] compared to placebo (n = 3). The two CB1R antagonists/inverse agonists tested in schizophrenia had no significant effects on psychopathology and cognition. Rimonabant and drinabant (AVE1625) were withdrawn from worldwide marketing due to psychiatric side effects [45]. Altogether, cannabidiol plus existing antipsychotic medication showed beneficial effects. Improvements in psychotic symptoms and cognition were not superior to antipsychotic medication or placebo in 3 studies. More studies with larger sample sizes are needed to systematically investigate these effects.

Generalized social phobia (ICD 10 F40.11) One systematic review [90] including 1 RCT [11]. This RCT tested the effects of one experimental session of a simulated public speaking test on treatment-naive individuals with generalized social anxiety disorder (n = 36). Participants received either a single dose of CBD (600 mg; n = 12) or placebo (n = 12). Both groups were compared to healthy controls (n = 12). Subjective ratings on the Visual Analogue Mood Scale (VAM) [33, 88] and physiological measures (blood pressure, heart rate, skin conductance) were measured at six different time points during the tests. Medication with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort and alert levels when compared with the control group. No significant differences were observed between the CBD group and healthy controls in the negative self-statement scores, cognitive impairment, discomfort, and alert factors. The increase in anxiety induced by the public speaking tests on subjects with generalized social anxiety disorders was reduced with the use of CBD, resulting in a similar response as the healthy controls. No adverse effects were found for CBD. More studies with larger sample sizes are needed to replicate the results of this study.

Posttraumatic stress disorder (ICD 10 F43.12) One RCT (n = 10 participants) [36] assessed recurrent distressing nightmares in a sample of Canadian male military personnel with PTSD (DSM-IV). The intervention was nabilone (0.5 mg, titrated to the effective dose (nightmare suppression) or reaching a maximum of 3.0 mg/7 weeks). Subjects were allowed to continue psychotherapy and any other medication. The mean reduction in nightmares as measured by the CAPS Recurring and Distressing Dream scores [14] were − 3.6 ± 2.4 and − 1.0 ± 2.1 in the intervention and control group (p = 0.03). Mean global improvement as measured by the Clinical Global Impression of Change (CGI-C) [17] was 1.9 ± 1.1 (i.e., much improved) and 3.2 ± 1.2 (i.e., minimally improved) in the intervention and control group (p = 0.05). Five out of 10 (50%) were much improved on nabilone vs. 1 out of 9 (11%) on placebo. For the General Well-Being Questionnaire [71] improvements were 20.8 ± 22 and − 0.4 ± 20.6 in the nabilone and placebo groups, respectively (p = 0.04). No improvement of sleep intensity and quality was reported. Every second participant reported adverse events (nabilone group: 50%; control group: 60%). No event was severe nor resulted in a drop-out. More studies with larger sample sizes are needed to replicate these study results.

Anorexia nervosa (ICD 10 F50.0) One systematic review [28] of 1 RCT [5–7] was found. This study tested the effects of dronabinol (2 × 2.5 mg/day; 4 weeks) as add-on to standard psychotherapy and eating management in a sample of women with severe (> 5 years) anorexia nervosa (DSM-IV-TR) (n = 25). Primary outcomes were weight, behaviors and beliefs (Eating-Disorder Inventory II) [78] as well as physical activity. The trial found weight gain in both groups, with larger effects in the active treatment group (1 kg) vs placebo (0.34 kg). No changes were found in the Eating-Disorder Inventory and in the duration of physical activity. Adverse effects were reported in both groups (no serious adverse effects). More studies with larger sample sizes are needed to replicate these results.

Attention-deficit hyperactivity disorder (ADHD) (ICD 10 F90) The effects of Nabiximols compared to placebo were tested in one RCT (n = 30 adults) [18]. Patients currently treated with stimulants were asked to stop their medication for 1 week before their baseline assessments and for the duration of the study. Patients on long-acting medications, such as atomoxetine, were excluded from the study. The primary outcome was cognitive performance and activity level; secondary outcomes included ADHD and emotional lability symptoms. For the primary outcome, no significant difference was found (ITT-analysis) (Est = − 0.17, 95% CI − 0.40 to 0.07, p = 0.16). For secondary outcomes, improvements in hyperactivity/impulsivity (p = 0.03) and a cognitive measure of inhibition (p = 0.05) were found, but not in inattention (p = 0.10) or emotional lability (p = 0.11). Results did not meet significance following adjustment for multiple testing. One serious (muscular seizures/spasms) and three mild adverse events occurred in the active group and one serious adverse event (cardiovascular problems) in the placebo group. More studies with larger sample sizes are needed to replicate the results of this study.

Tourette’s disorder (ICD 10 F95) One systematic review [90] identified 2 RCTs (3 reports, n = 36 Patients) [60–62] in which therapy-resistant Tourette`s disorder (n = 12/n = 24) were assessed. The interventions were THC (1 × max. 10 mg) and THC (titrated to 10.0 mg/day, 6 weeks), respectively. Comparisons were placebos (identical in taste and appearance). Multiple outcome variables were assessed (e.g., Tourette`s Syndrome Clinical Global Impressions Scale), Shapiro Tourette-Syndrome Severity Scale, Yale Global Tic Severity Scale (YGTSS) [87]. Both studies found improvement in various Tourette-related outcomes, of which not all reached statistical significance. Adverse effects were reported in both groups (no serious adverse effects). More studies with larger sample sizes are needed to replicate the results of these two studies.

Due to a large heterogeneity of patient groups, interventions, comparisons and outcome criteria, data were not sufficient to calculate effect sizes and odds ratios.