The therapeutic role of Cannabidiol in mental health: a systematic review
0000 0000 9363 9292grid.412080.fDow University of Health Science, Karachi, Pakistan
0000 0001 2177 6375grid.412016.0Psychiatry and Behavioral Sciences, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS KS 66160 USA
PICACS Clinic, Bothell, WA USA
0000 0004 0608 7688grid.412129.dKing Edward Medical University, Lahore, Pakistan
Child and Adolescent Psychiatrist, KVC Hospitals, Kansas, USA
Abstract
Background
The therapeutic application of cannabidiol (CBD) is gaining interest due to expanding evidence for its use.
Objective
To summarize the clinical outcomes, study designs and limitations for the use of CBD and nabiximols (whole plant extract from Cannabis sativa L. that has been purified into 1:1 ratio of CBD and delta-9-tetrahydrocannabinol) in the treatment of psychiatric disorders.
Materials and method
A systematic review was conducted including case reports, case series, open-label trials, non-randomized and randomized controlled trials (RCTs). The search resulted in 23 relevant studies on CBD and nabiximols in the treatment of a wide range of psychiatric disorders. The quality of evidence was judged by using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence that ranges from Level 1 to Level 5 based on the quality and study design. These levels of evidence help in grading the recommendations, including Grade A (strong), Grade B (moderate), Grade C (weak), and Grade D (weakest).
Results
CBD and CBD-containing compounds such as nabiximols were helpful in alleviating psychotic symptoms and cognitive impairment in patients with a variety of conditions, and several studies provided evidence of effectiveness in the treatment of cannabis withdrawal and moderate to severe cannabis use disorder with Grade B recommendation. There is Grade B recommendation supporting the use of CBD for the treatment of schizophrenia, social anxiety disorder and autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). Grade C recommendation exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These recommendations should be considered in the context of limited number of available studies.
Conclusion
CBD and CBD-containing compounds such as nabiximols were helpful in alleviating symptoms of cannabis-related disorders, schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD with moderate recommendation. However, there is weaker evidence for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. The evidence for the use of CBD and CBD-containing compounds for psychiatric disorders needs to be explored in future studies, especially large-scale and well-designed RCTs.
Introduction
Cannabis sativa, a species of cannabis plant, is well known to humankind, with its earliest use in ancient Chinese culture dating as far back as 2700 B.C. (Zuardi, 2006). The use of medical cannabis in China was reported in the world’s oldest pharmacopoeia (Martin et al., 1999). However, interest in the role of cannabis flourished in the late twentieth century after the recognition of an endogenous cannabinoid system in the brain (Zuardi, 2006; Martin et al., 1999). More recently, research has centered on the description and cloning of specific receptors and the therapeutic effects of medical cannabis, and different cannabinoids in the cannabis plant have gained interest (Martin et al., 1999). Recent studies have focused on the therapeutic role of medical cannabis in different disorders. As a result, there is a growing need to summarize and review the evidence for its therapeutic and adverse effects as an aid to public health policy development, and to provide direction and impetus to pharmaceutical research in this field.
The cannabis plant has more than 140 cannabinoid compounds, with Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) attracting significant interest (Citti et al., 2018). Δ9-THC is the primary psychoactive ingredient, and CBD is a non-intoxicating ingredient (Zuardi, 2006; Citti et al., 2018). Evidence from preclinical studies suggested that CBD had potential therapeutic benefits ranging from antiinflammatory to neuroprotective, antipsychotic, analgesic, anticonvulsant, antiemetic, antioxidant, antiarthritic, and antineoplastic properties; for a review, see (Pertwee, 2006). CBD has several receptors and molecular targets. This compound antagonizes the action of CB1 and CB2 receptor agonist (Blessing et al., 2015; Peres et al., 2018). The CB1 and CB2 receptors are coupled negatively through G-proteins to adenylate cyclase and positively to mitogen-activated protein kinase (Pertwee, 2006). In addition to CB1 and CB2 receptor activity, CBD is an agonist of vanilloid receptor TRPV1. It also acts as an agonist of serotonin receptor 5-hydroxytryptamine (5-HT1A), an antagonist of G-protein-coupled receptor GPR55, and an inverse agonist of GPR3, GPR6, and GPR12 (Peres et al., 2018). Data from single-photon emission computed tomography showed CBD to exert anxiolytic effects by acting on paralimbic and limbic pathways (Crippa et al., 2011). The agonist effect of CBD on 5-HT1A also supports its anxiolytic and antidepressant properties (Russo et al., 2005). CBD inhibits enzymatic hydrolysis and anandamide uptake through its agonist action on CB1, CB2, and TRPV1 receptors (Peres et al., 2018). In addition, CBD indirectly enhances endogenous anandamide signaling by inhibiting the intercellular degradation of anandamide (Leweke et al., 2012). This endogenous neurotransmitter exerts antipsychotic effects in patients with schizophrenia (Leweke et al., 2012).
The pharmacokinetic profile of CBD has been extensively explored in the existing literature. A recently published systematic review of the pharmacokinetics of CBD found that the area under curve (AUC0 − t) and maximum serum concentration (Cmax) occurs between 1 and 4 h (Millar et al., 2018). The AUC0 − t and Cmax reach maximum values faster after smoking or inhalation compared to oral or oromucosal routes. Bioavailability was 31% after smoking, but no other studies reported the absolute bioavailability of CBD after other routes in humans. The half-life of CBD ranges between 1.4 and 10.9 h after oromucosal spray and 2–5 days after chronic oral administration (Millar et al., 2018). Fed states and lipid formulations increase Cmax (Millar et al., 2018). The bioavailability of oral CBD ranges between 11 and 13%, compared to 11 to 45% (mean 31%) via inhalation (Scuderi et al., 2009). CBD is well-tolerated, yet despite a relatively lower risk of drug–drug interactions, it should be used cautiously in combination with drugs metabolized by the CYP3A4 and CYP2C19 pathways, and the substrates of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 (Millar et al., 2018). The clinical relevance of these interactions needs to be explored in future studies (Brown & Winterstein, 2019).
Dronabinol and nabilone are synthetic in origin, whereas nabiximols is plant-based (Papaseit et al., 2018). The percentage of THC and its ratio to CBD (THC/CBD ratio) defines the potency and psychoactive effects of a given formulation (Papaseit et al., 2018). Those with higher CBD/Δ9-THC ratios have euphoric, anxiolytic, and relaxing effects, whereas lower CBD/Δ9-THC ratios have sedative properties (Papaseit et al., 2018). Nabiximols, a CBD-containing compound, contains Δ9-THC and CBD at a 1:1 ratio (Papaseit et al., 2018). The Food and Drug Administration has approved Epidiolex® (an oral formulation of CBD) for two forms of childhood seizures (Lennox–Gastaut syndrome and Dravet syndrome) in children 2 years of age and older (Papaseit et al., 2018).
Previous efforts to synthesize the evidence for medical cannabis use in patients with psychiatric disorders have been published (Hoch et al., 2019; Lowe et al., 2019). For example, Hoch et al. conducted an excellent systematic review that summarized four systematic reviews and 14 randomized controlled trials (RCTs), but did not consider non-clinical trial evidence (case reports and case series) (Hoch et al., 2019). A review by Mandolini et al. recently summarized the clinical findings from 14 studies of psychiatric disorders, but these authors did not provide information about nabiximols (Mandolini et al., 2018). In contrast to the review articles noted above, the present article aims to provide a more comprehensive review of the use of CBD and CBD-containing compounds such as nabiximols to treat psychiatric disorders. The present review included studies focused on schizophrenia, cannabis-related disorders, attention deficit hyperactivity disorder (ADHD), comorbidities in autism spectrum disorder (ASD), social anxiety disorder (SAD), other anxiety disorders, insomnia, bipolar disorder, post-traumatic stress disorder (PTSD), psychosis in Parkinson’s disease, and Tourette syndrome. This article broadly reviews the efficacy, safety, and psychiatric benefits of CBD and CBD-containing compounds (nabiximols). We distinguish clearly here between the clinical findings for CBD and nabiximols, as the latter also contains THC.
Methods
Eligibility criteria
The main inclusion criterion was studies of the psychiatric use of CBD and CBD-containing compounds such as nabiximols. Only case reports, case series, retrospective chart reviews, open-label trials, and RCTs were considered. All books, conference papers, theses, editorials, review articles, metaanalyses, in-vitro studies, laboratory studies, animal studies, studies of participants without psychiatric disorders, and abstract-only articles were excluded. No restrictions on language, country, publication year, or patients’ age, gender, or ethnicity were applied.
Search strategy
Eight electronic databases were searched on October 28th, 2018: PubMed, Scopus, Web of Science, POPLINE, New York Academy of Medicine Grey Literature Report, PsycINFO, Psycarticles, and CINAHL. The following search strategy was used in all cases: (CBD OR Cannabi* OR nabiximols) AND (psychiat* OR Depress* OR Anxiety OR Psycho* OR schizo* OR Bipolar OR Substance OR ADHD OR Attention OR Autism) AND (treatment). The manual search of references of included studies was performed by four independent reviewers.
Study selection
The search results from the eight databases were imported to Endnote v. 7 (Thompson Reuters, CA, USA) to remove any duplicates. Four independent reviewers (RK, NM, AF, MAF) screened the titles and abstracts (when available), followed by full-text screening of each included article with the predetermined eligibility criteria. All articles included after full-text screening were then searched manually. Discrepancies were resolved by consensus through discussion among reviewers, or with guidance from a third reviewer (SN).
Data extraction and grading
The data were extracted independently by the authors, and were cross-checked by discussion among the four reviewers (RK, NM, AF, MAF), with guidance from the senior author (SN) in case of discrepancy. The data were categorized as pertaining to target diagnosis, study design, sample size, duration of the trial, age range, dose ranges, measurement scales, clinical outcomes, study limitations, and common side effects.
The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade the quality of evidence (OCEBM, 2019). Level 1 evidence is for systematic review of RCTs or individual RCT of narrow confidence interval, Level 2 for cohort studies or systematic review of cohort studies, Level 3 for case-control studies or systematic review of case-control studies, and Level 4 for case-series for studies focused on therapy, prevention, etiology and harm (OCEBM, 2019). These levels of evidence are used to generate Grades of Recommendation. Grade A is for consistent level 1 studies, Grade B for consistent level 2 or 3 studies or extrapolations from level 1 studies, and Grade C for level 4 studies or extrapolations from level 2 or 3 studies. Grade D is ranked for level 5 evidence or inconsistent or inclusive studies of any level (OCEBM, 2019).
Results & discussion
The search of eight electronic databases and our manual screening method generated 511 results. After the removal of duplicates, titles and abstracts were screened, resulting in the exclusion of 459 articles. Full-text screening of 52 articles was performed, and 23 articles meeting the inclusion criteria were analyzed. Figure 1 summarizes the screening process.
Of the 23 articles, there were eight RCTs, one clinical trial, four open-label trials, one retrospective chart review, seven case reports, and two case series, comprising a total patient population of 526. The studies focused on CBD and nabiximols use in the treatment of schizophrenia, cannabis-related disorders, ADHD, ASD and comorbidities, anxiety, insomnia, SAD, bipolar disorder, PTSD, psychosis in Parkinson’s disease, and Tourette syndrome. No studies of substance use disorders other than cannabis use were identified. In this review article, the authors have used DSM-5 terminologies for most of the disorders except for DSM-IV-Text Revised terminology of substance dependence. A comparable DSM-5 terminology of moderate-severe substance use disorder was used in this case.
Qualitative synthesis of eligible studies
Schizophrenia and psychosis in Parkinson’s disease
There were three RCTs (164 patients), one clinical trial (27 patients), one case series (three patients), one case report for schizophrenia, and one open-label trial (six patients) for psychosis in Parkinson’s disease (Table 1) (Leweke et al., 2012; Hallak et al., 2010; Boggs et al., 2018; McGuire et al., 2018; Zuardi et al., 2006; Zuardi et al., 1995; Zuardi et al., 2009). Of the seven studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in one case report and one case series (OCEBM, 2019). Since most of the studies were from level 2 and level 3 evidence, there is Grade B recommendation for schizophrenia. The dose of CBD in these studies ranged from 200 to 1500 mg daily. The highest dose was titrated to 1500 mg daily as reported by Zuardi and colleagues (Zuardi et al., 1995). Irrespective of the study design, three studies reported that CBD alleviated psychotic symptoms and cognitive impairment in patients with chronic cannabis use and Parkinson’s disease (Leweke et al., 2012; Zuardi et al., 1995; Zuardi et al., 2009), while only two RCTs and one clinical trial provided evidence for the effectiveness of CBD among patients with schizophrenia, albeit with mixed results (Leweke et al., 2012; McGuire et al., 2018; Zuardi et al., 2009).
Author Diagnosis Pharmacological agent Study design Strength of evidence* Group (n) Duration Age range (years) Dose range (mg) Scales to measure the clinical outcome Clinical outcome Common side effects Reference number Hallakal., 2010 Schizophrenia CBD RCT Level 2 CBD 300 mg = 9CBD 600 mg = 8Placebo = 10 1 month > 18 CBD = 300 or 600 mg SCWT - The SCWT and skin conductance were recorded at baseline and 1 month after the initial test. Patients received CBD or placebo before the test.- In the first session, there was significant SCWT effect on electrodermal response factor only (F1,16 = 5.98; p < 0.05) related to time taken to complete board I.- The mean time required for the responsive group was 77.8 (SEM = 11.7) and for the non-responsive it was was 119.7 (SEM = 12.3).- In the second assessment, a significant effect for number of errors on board II (F2,16 = 6.027; p = 0.014). The group that received CBD 600 mg had a higher score compared to the other two.- SCWT score improved in the placebo and 300 mg group, but the improvement was smaller in the 600 mg CBD group.The improvement in participants given CBD 600 mg was smaller due to sedation. No side effects were reported. 18 Leweke et al., 2012 Schizophrenia CBD RCT Level 2 CBD = 20Amisulpride = 19 4 weeks 18–50 - Participants were started on 200 mg/day of CBD or amisulpride- The dose was increased by 200 mg/day in the 1st week.- The total dose was 200 mg four times daily (800 mg/day) BPRS, PANSS, EPS, serum prolactin, body weight - Patients in both groups reported a comparable improvement in PANSS and BPRS (1.0, 95% confidence interval 12.6 to 14.6, P = 0.884.- CBD inhibited FAAH activity and increased intrinsic anandamide signaling, resulting in antipsychotic properties. There was a a statistically significant association between higher anandamide levels and decrease in psychotic symptoms in patients treated with cannabidiol (P = .0012) Treatment with CBD was associated with lower risk of EPS, less weight gain, and a lower increase in prolactin level - a predictor of galactorrhea and sexual dysfunction. 9 Boggs et al., 2018 Schizophrenia CBD RCT Level 2 CBD = 18Placebo = 18 6 weeks 18–65 CBD = 600 mg/day MCCB, PANSS - For MCCB Composite score, there was no effect of drug or time, but a significant drug × time effect was observed (F (1, 32) = 5.94; p = 0.02).- There was only improvement in placebo-treated subjects time (F (1, 32) = 4.84; p = 0.03).- Lack of improvement in psychotic symptoms on PANSS (F (3, 101) = 1.66; p = 0. 18). Mild sedation was reported in 20% of participants compared to 5% in placebo. 22 McGuire et al., 2018 Schizophrenia CBD RCT Level 2 CBD = 43Placebo = 45 6 weeks 18–65 1000 mg/day PANSS, SANS, CGI, GAF, BACS - The percentage of responders (patients with an improvement 20% in PANSS total score) was high in CBD group compared to placebo group, however, it could not reach statistical significance.- About 78.6% of participants improved in CBD group on CGI-I scores (CGI-I: treatment difference = 20.5, 95% CI = − 0.8, − 0.1 p = 0.018) compared to 54.6% in placebo arm.- CBD group had an improvement in their global functioning (treatment difference = 3.0, 95% CI = -0.4, 6.4; p = 0.08) and cognitive performance (treatment difference = 1.31, 95% CI = − 0.10, 2.72; p = 0.068), however, it could not reach statistical significance. Mild transient GI discomfort, hyperlipidemia. 23 Zuardi et al., 2006 Schizophrenia CBD Case series Level 4 3 45 days 22–23 1–5 days = Placebo6–35 days = Participants were started on 40 mg twice a day, titrated to 1280 mg/day depending on efficacy and tolerability.36–40 days = Placebo Last 15 days = Olanzapine BPRS, PANSS, CGI - Case 1: During CBD phase, symptoms improved at 1280 mg/day, followed by worsening of symptoms after CBD discontinuation.- Case 2: No improvement with CBD and partial improvement with olanzapine, requiring clozapine.- Case 3: Slight improvement with CBD. However, this patient failed to respond to olanzapine, clozapine, or haloperidol decanoate. No side effects were reported. 24 Zuardi et al., 1995 Schizophrenia CBD Case report Level 4 1 4 weeks 19 1–4 days: Placebo4–30 days: CBD oil was increased to 1500 mg/day in divided doses.31–34 days: PlaceboAfter 35 days: Haloperidol was started. BPRS - Open BPRS scores improved from 42 to 13 and blind BPRS scores improved from 50 to 30, for an improvement of 69 and 69%, respectively.- Improvements in following factors of BPRS: thought disturbance (62.5 to 25%), hostility-suspiciousness (83.3 to 33.3%), anxiety-depression (62.5 to 18.8%), activation (58.3 to 16.7%), and anergia (31.3 to 0.0%). No side effects were reported. 25 Zuardi et al., 2009 Psychosis in Parkinson’s disease CBD Open-label pilot study Level 3 6 4 weeks Mean age 58.8 ± 14.9 years The initial dose of 150 mg was increased to 400 mg at the end of week 4, with an increase of 150 mg/week. BPRS, PPQ - There was an improvement on total scores of BPRS (P < 0.001) and four BPRS factors scores (Thinking disorder p = 0.002, Withdrawal-retardation P = 0.007, Anxious-depression p = 0.003, Activation p = 0.005) including positive and negative symptoms.- A reduction in scores of PPQ (P = 0.001) was observed at the endpoint of study. No adverse effect on cognitive functioning was reported. 26
In a clinical trial, Hallak and colleagues suggested an improvement in schizophrenia-associated cognitive impairment with a CBD dose of 300 mg/day, while no significant improvement was seen at a CBD dose of 600 mg/day (Hallak et al., 2010). In another RCT, McGuire and colleagues found that CBD (1000 mg/day) improved positive psychotic symptoms, but failed to improve negative symptoms and general psychopathology associated with this illness (McGuire et al., 2018). In another RCT, Boggs and colleagues found that CBD (600 mg/day) failed to improve outcomes pertaining to reasoning and problem-solving domains (Boggs et al., 2018).
In a comparison of CBD with amisulpride, Leweke and colleagues reported similar improvements in patients taking CBD 800 mg/day and those taking amisulpride (Leweke et al., 2012). This study also indicated an increase in intrinsic anandamide signaling, an effect that explained the antipsychotic properties of CBD (Leweke et al., 2012). Moreover, CBD treatment was associated with a lower risk of extrapyramidal symptoms, less weight gain, and a lower increase in prolactin, which is a predictor of galactorrhea and sexual dysfunction (Leweke et al., 2012). An open-label study of CBD to treat psychosis in Parkinson’s disease also suggested promising results at a dose of 400 mg daily; however, there was a strong risk of bias because of inadequate blinding of participants, personnel and outcome assessors (Zuardi et al., 2009).
The remaining evidence comprised two minimal quality case reports and case series. Zuardi and colleagues were the first to report favorable findings for CBD in patients with schizophrenia (Zuardi et al., 1995). The dose of CBD ranged from 600 to 1500 mg daily in schizophrenia studies. A case series of three patients with treatment-resistant schizophrenia found improvement in only one patient (Zuardi et al., 2006). In the first case, there was an improvement in psychotic symptoms with CBD at 1280 mg/day; however, the symptoms worsened after CBD was discontinued. In second case, CBD was ineffective for the symptoms. Patient had an improvement in symptoms with clozapine. In the third case, no improvement with CBD and partial improvement with olanzapine were observed, although clozapine was subsequently required. In case 3, mild improvement was reported with CBD in a patient who had previously failed to respond to olanzapine, clozapine, or haloperidol decanoate. These results suggest a limited role of CBD in treatment-resistant schizophrenia (Zuardi et al., 2006). The dose were not individually mentioned for case 1 and 2.
Four of the included studies did not report any adverse effects of CBD among patients with psychosis. CBD was well-tolerated in these patients except for mild transient sedation, hyperlipidemia, and gastrointestinal distress. Patients with schizophrenia had fewer instances of extrapyramidal symptoms, less weight gain, and a lower increase in prolactin levels.
CBD is postulated to improve cognitive performance in psychosis through the mediation of CB1 and CB2 receptor agonism at lower concentrations (Hallak et al., 2010; Solowij et al., 2018; Manseau & Goff, 2015). This cognitive improvement has been hypothesized due to the higher concentration of cannabinoid receptors in the hypothalamus, suggesting a role in superior cognitive functioning (Hallak et al., 2010). Naturalistic studies of CBD report better cognitive performance including memory, increased grey matter in the hippocampus, and fewer psychotic symptoms in patients given higher doses of CBD (Solowij et al., 2018).
The therapeutic benefits for psychosis is hypothesized due to the inhibition of anandamide re-uptake and degradation, resulting in increased anandamide levels in the brain (Manseau & Goff, 2015). Increased anandamide levels and improvements in the symptoms of psychosis were reported in another 4-week-long RCT comparing the efficacy of CBD to amisulpride for the treatment of schizophrenia (Leweke et al., 2012). Interestingly, anandamide levels were elevated in patients with acute schizophrenia compared to chronic schizophrenia, indicating a compensatory increase in an acute state (Giuffrida et al., 2004).
Other disorders
The present review included two RCTs (54 patients), one open-label trial (53 patients), one retrospective chart review (72 patients), and four case reports for CBD and nabiximols use in the treatment of other psychiatric disorders. Specifically, this review looked at ADHD (one RCT), comorbidities in ASD (one open-label trial), anxiety and sleep problems (one retrospective chart review), SAD (one clinical trial), bipolar disorder (one case report), PTSD (one case report), and Tourette syndrome (two case reports), as summarized in Table 3 (Cooper et al., 2017; Barchel et al., 2018; Bergamaschi et al., 2011; Shannon et al., 2019; Zuardi et al., 2010; Shannon & Opila-Lehman, 2016; Trainor et al., 2016; Pichler et al., 2019). Of the nine studies, level 2 evidence was found in two RCTs, level 3 evidence in one clinical trial, and level 4 evidence in one retrospective chart review, four case reports (OCEBM, 2019). There is Grade B recommendation for comorbidities in patients with ASD, anxiety disorders including SAD and sleep problems, and ADHD where as bipolar disorder, PTSD and Tourette Syndrome has Grade C recommendation. However, this should be considered in the context of fewer studies of each these diagnoses.
Author Diagnosis Study design Pharmacological agent Strength of evidence Group (n) Duration Age range (years) Dose range (mg) Scales to measure the clinical outcome Clinical outcome Common side effects Reference number Cooper et al., 2017 ADHD RCT Nabiximols Level 2 Nabiximols = 15Placebo = 15 6 weeks 18–55 Nabiximols oromucosal spray = 2.7 mg Δ9-THC and 2.5 mg CBDMean dose = 4.7 sprays per dayMaximum dose = 14 sprays/day QbTest - The experimental group had better scores compared to placebo group (Est = 0.17, 95%CI-0.40 to 0.07, p = 0.16, n = 15/11 active/placebo).- Nabiximols was associated with a nominally significant improvement in hyperactivity/impulsivity (p = 0.03) and a cognitive measure of inhibition (p = 0.05), and a trend towards improvement for inattention (p = 0.10) and executive learning (p = 0.11). Muscular seizures and spasms 34 Barchel et al., 2018 ASD and related comorbidities1. Hyperactivity2. Sleep problems3. Self-injury4. Anxiety Open-label trial CBD and Δ9-THC Level 3 53 30–588 daysMedian duration = 66 days 4–22Median age = 11 years CBD oil solution with CBD and Δ9-THC at 1:20 ratioCBD16 mg/kg (maximal daily dose 600 mg)CBD median IQR daily dose = 90 (45–143) mgΔ9-THC0.8 mg/kg (maximal daily dose 40 mg).THC median IQR daily dose = 7 (4–11) mg Not mentioned - These patients were taking concomitant medications including stimulants, antipsychotics, anti-epileptics, melatonin, anti-depressants, alpha-agonists, and anti-muscarinic agents.- Out of 53 patients, 74.5% reported improvement in comorbid symptoms.- About 68.4% reported improvement in hyperactivity, 67.6% in self-injurious behaviors, 71.4% in sleep problems, and 47.1% in anxiety symptoms. Somnolence and change in appetite 35 Bergamasci et al., 2011 Anxiety related to public speaking RCT CBD Level 4 CBD = 12Placebo = 12 Single dose SAD-placebo = 22.8SAD-CBD = 24.6Healthy = 23.3 600 mg Mini-SPIN, VAMS, SSPS, SSPS-N, BSS - Pretreatment with a single dose of CBD significantly decreased anxiety, cognitive impairment and discomfort in speech performance. It also resulted in significantly decreased alertness in anticipatory speech.- There were significant effect of phases (F3.6,118.51/432.7; p < 0.001), group (F2,331/413.5; p < 0.001) and phases by group interaction (F7.2,118.5 1/4 6.4; p < 0.001).- There were also significant differences between placebo and healthy control group at the initial (p < 0.018), anticipatory (p < 0.001), speech (p < 0.001) and post-speech (0.018) phases.- The CBD group differs from the placebo (p < 0.012) and control (p < 0.007) groups during the speech phase No side effects were reported. 36 Shannon et al., 2019 Anxiety and insomnia Retrospective chart review CBD Level 4 Anxiety = 47Sleep disorder = 25 3 months Sleep disorder = 18–72Mean age = 36.5 yearsAnxiety = 18–70Mean age = 34 years 25–175 mgMost patients received 25 mg/day HAM-A, PSQI - Most patients received 25 mg/day CBD; a handful of patients received 50 or 75 mg/day. One patient with schizoaffective disorder and trauma was given up to 175 mg/day.- After 1 month of treatment, 79.2 and 66.7% of patients reported improvement in anxiety and sleep, respectively.- After 2 months, 78.1 and 56.1% of patients reported improvement in anxiety and sleep, respectively, which were also observed at 3-month follow-up.- Greater improvement in anxiety scores than sleep scores. - 2 patients discontinued treatment due to fatigue and 1 patient with a development disorder had increased sexually inappropriate behaviors, resulting in discontinuation- Transient mild sedation was also reported in some patients. 37 Zuard et al., 2010 Bipolar disorder Case report CBD Level 4 2 38 days 34 and 36 1–5 days for both participants: PlaceboCase 1:5–19 days: CBD 600 mg and olanzapine 10–15 mg20–33 days: CBD 900–1200 mgCase 2:5–33 days: CBD 600–1200 mg33–38 days: Placebo BPRS, YMRS - Case 1: 37 and 33% improvement on BPRS and YMRS with CBD and olanzapine, but no additional improvement with CBD monotherapy.- Case 2: CBD failed to improve symptoms of bipolar disorder at any of the prescribed doses. No side effects were reported. 38 Shannon & Opila-Lehman., 2016 Posttraumatic stress disorder Case report CBD Level 4 1 5 months of CBD 10 CBD oil 25 mgLiquid CBD 6–12 mg sublingual spray as needed for anxiety SDSC, SCARED - CBD scores improved from 34 to 18 at endpoint, indicating no anxiety.- Sleep Disturbance Scale scores improved from 59 to 38, suggesting no problem with sleep. No side effects were reported. 39 Trainor et al., 2016 Tourette syndrome Case report Nabiximols Level 4 1 4 weeks 26 Two oromucosal sprays of nabiximols BIDTotal dose = 10.8 mg Δ9-THC, 10 mg CBD per day YGTSS, ORVRS - Using the ORVRS to evaluate tics, motor tics were reduced by 85% and vocal tics by 90%- Number of affected body areas decreased.- mprovement of 35% on YGTSS. No side effects were reported. 40 Pichler et al., 2018 Tourette syndrome Case report Cannabis tinctureTHC combined with CBD Level 4 1 2 months 47 34 drops cannabis tincture 3 times a day = 10 mg Δ9-THC combined with 20 mg of CBD YGTSS - With the combination of Δ9-THC and CBD, there was significant improvement in tic frequency and severity.- Scores decreased from 73/100 to 44/100 on YGTSS.- Patient reported improvement in quality of life and enhanced social activity. Slight xerostomia 41
The oromucosal nabiximols spray was tested to evaluate its effects on cognitive performance, hyperactivity, inattention, and emotional lability in 15 participants in a placebo-controlled RCT (Cooper et al., 2017). The mean dose of nabiximols was 4.7 sprays per day (2.7 mg Δ9-THC and 2.5 mg CBD). Although an improvement in these symptoms was observed in the intervention group, it failed to reach statistical significance (Cooper et al., 2017). However, this result may not be valid or reliable due to the low power of the study.
One case report on the use of CBD by two patients with bipolar disorder showed limited to no improvement with doses of 600–1200 mg for bipolar mania in one of the patients (Shannon et al., 2019). The second patient was prescribed CBD 600 mg (5–9 days) and olanzapine (10–15 mg), followed by CBD 900–1200 mg (20–33 days), and showed improvement on the Brief Psychiatric Rating Scale (37% reduction) and Young Mania Rating Scale (33% reduction) with CBD and olanzapine, but no additional improvement with CBD monotherapy (Shannon et al., 2019). This effect was consistent with results from animal studies that modeled acute mania with dextroamphetamine (Shannon et al., 2019). The lack of effectiveness can be attributed to the shorter duration of treatment in both cases. This evidence from studies of bipolar mania should be considered in the context of different pharmacological agents responding differently to certain episodes of bipolar disorder. In animal studies, CBD induced a rapid, persistent antidepressant response by increasing brain-derived neurotrophic factor in the prefrontal cortex (Shannon et al., 2019). Given its possible antidepressant benefits, the role of CBD should be explored in unipolar and bipolar depression.
In an open-label trial involving children with ASD, Barchel and colleagues reported that a solution of CBD and Δ9-THC (1,20 ratio) was effective for hyperactivity, insomnia, self-injurious behaviors, and anxiety (Barchel et al., 2018). The median dose was 90 mg with an interquartile range (IQR) of 45–143 mg for CBD whereas The medical dose was 7 mg with IQR of 4–11 mg. In this cohort of 53 patients, 74.5% showed improvement in their comorbid symptoms, 68.4% in hyperactivity, 67.6% in self-injurious behaviors, 71.4% in sleep problems, and 47.1% in anxiety symptoms. This treatment regimen lasted for a median of 66 days. However, Salgado and Castellanos suggested guiding principles for the use of CBD in this population, including a better clinical understanding of CBD, open discussion with parents and patients, addressing their perceptions, promoting informed consent, and exercising caution in the use of CBD (Salgado & Castellanos, 2018). Patients with ASD make up a heterogeneous group of individuals with different comorbidities that should be considered.
The efficacy of CBD for SAD and PTSD was explored in three studies including one RCT, one case report, and one chart review. The RCT reported the results of a simulated public speaking test among 12 healthy control participants and 24 patients with SAD who received a single dose of CBD 600 mg or a placebo before the test. This study reported that pretreatment with CBD resulted in less anxiety, cognitive impairment, and discomfort during their speaking performance. It also resulted in a significant reduction in alertness in their anticipatory speech compared to the placebo group (Bergamaschi et al., 2011).
In a 10-year-old patient, 5 months of treatment with CBD oil (25 mg) and liquid CBD (6–12 mg) in a sublingual spray as needed was associated with less anxiety and better sleep quality, with no adverse effects (Shannon & Opila-Lehman, 2016). These results were replicated for anxiety in a recently published chart review of 72 adult patients with insomnia and anxiety (Shannon et al., 2019). Most patients in this group were given 25 mg CBD/day, while a few patients were given 50 or 75 mg/day, and one patient with schizoaffective disorder and trauma was given up to 175 mg/day. All patients showed less anxiety and improved sleep, with reductions of 65–80% in the Hamilton Anxiety Rating Scale and Pittsburgh Sleep Quality Index scores.
Nabiximols produced improvements in patients with Tourette syndrome at a much lower dose than what was used for cannabis-related disorders (Trainor et al., 2016; Pichler et al., 2019). These case reports tested two oromucosal nabiximols sprays used twice a day (total dose 10.8 mg Δ9-THC and 10 mg CBD per day) (Trainor et al., 2016), and the second also tested cannabis tincture (34 drops three times a day (Pichler et al., 2019). Both case reports found improvements in tic frequency (Trainor et al., 2016; Pichler et al., 2019), severity (Trainor et al., 2016; Pichler et al., 2019), quality of life, and social activity (Trainor et al., 2016). These treatments regimens were used for 4 weeks with the oromucosal spray form (Trainor et al., 2016) and 8 weeks for cannabis tincture (Pichler et al., 2019). The therapeutic benefits can be attributed to the anxiolytic and sleep-inducing properties of CBD (Trainor et al., 2016). It is difficult to ascertain whether these improvements were due to due to CBD, Δ9-THC, additive, or synergetic effects. The anxiolytic properties of CBD explain the attenuation of anxiety associated with the onset of tics, and the improvement in tics with a combination of Δ9-THC and CBD (Trainor et al., 2016; Pichler et al., 2019).
Adverse effects were reported in four of the studies, and included muscular seizures and spasms (Cooper et al., 2017), somnolence and changes in appetite (Barchel et al., 2018), fatigue, and sexually inappropriate behavior in a patient with developmental disorder (Shannon et al., 2019), mild sedation (Zuardi et al., 2010), and mild xerostomia (Pichler et al., 2019).
Summary of evidence
The present article provides a comprehensive review of the evidence supporting the use of CBD and CBD-containing compounds such as nabiximols to treat psychiatric disorders. CBD and nabiximols were effective in cannabis use-related disorders, and preliminary evidence was found in support of their use for other psychiatric disorders. Of the 23 studies reviewed here, level 2 evidence was found in eight RCTs, level 3 evidence in four open-label trials and one clinical trial, and level 4 evidence in one retrospective chart review, seven case reports, and two case series, according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (OCEBM, 2019). This review covers the evidence for different routes of administration, e.g. oral, inhalation spray, and sublingual. The bioavailability of these routes (11–13% for oral vs. 11–43% for inhalation) varies significantly – a factor that can impact the efficacy of different formulations.
Their antipsychotic, neuroprotective, anxiolytic, and sedating properties suggest a potential therapeutic role of CBD and nabiximols to treat various psychiatric disorders. The use of CBD at higher doses (above 1200 mg per day) showed promising results in case studies of schizophrenia and psychosis in patients with Parkinson’s disease, except in treatment-resistant cases. Regarding the use of CBD to treat anxiety disorders, its anxiolytic effect can help patients with PTSD-related and social performance-related anxiety, and nabiximols can reduce the anxiety associated with the onset of tics. There is also favorable evidence in patients with ASD for reducing hyperactivity, self-injurious behaviors, anxiety, and insomnia. Nabiximols showed no credible effect in the treatment of ADHD, while CBD was also found to be ineffective for bipolar disorder. Of all the cases examined, the strongest evidence was found for the treatment of cannabis-related disorders. The use of nabiximols yielded positive results in multiple studies of moderate to severe cannabis use disorder; however, the use of CBD alone has not been adequately documented outside a few cases and case series. Notably, CBD compounds were helpful in alleviating psychotic symptoms and improving cognitive impairment in patients across a variety of conditions.
Recommendations for future research
This review found low-level evidence for the use of cannabis and nabiximols in a variety of disorders. Despite our comprehensive literature search, only a few RCTs related to the disorders of interest were found. These RCTs were marred by a number of limitations, most importantly failure to blind the outcome assessor, participants, and research personnel (in the open-label trials). In addition, most RCTs had a small sample size, critically reducing the power of the study to draw robust conclusions. The findings of the RCTs reviewed here need to be validated via a series of larger, well planned, randomized, double-blinded, and placebo-controlled studies. The present report can be used to design and plan further studies; however, at present the use of CBD and nabiximols in clinical practice cannot be recommended with confidence due to the drawbacks noted above.
The evidence from studies included in this review can guide future trials by providing information pertaining to the dosages, formulations and routes of administration of CBD and nabiximols. Moreover, future studies should investigate different routes of administration in light of the differences in bioavailability. In view of the (albeit limited) evidence for treatment-resistant schizophrenia, the role of CBD should be explored in the early stages of psychosis or as an adjunct medication. Although CBD was ineffective for bipolar mania, its possible efficacy as an antidepressant should be assessed in studies focused on bipolar depression. Nabiximols has been helpful in cannabis-related disorder and Tourette syndrome, owing to the synergetic benefits of CBD and THC. Future studies designed to explore the comparative benefits of these treatments can shed further light on their clinical potential. Future RCTs should also consider adding first-line treatment agents as comparison arms, to ascertain the comparative efficacy of CBD in different mental disorders. Although fewer side effects were reported overall by patients in the studies reviewed here, the vulnerability to addiction to cannabinoids should not be ignored.
Limitations of the review
This review article has several limitations that should be considered. This review article provides evidence for CBD and CBD-containing nabiximols are two different pharmacological agents. Nabiximols has two active compounds and included studies do not consider the separate effects of THC VS CBD. There is need for future analyses to carefully consider their benefits individually. Only one-third of studies (8/23) in this review article are RCTs and most of these RCTs had a small sample size decreasing the power of the study to draw robust conclusions.
Conclusion
The evidence reviewed here favors CBD use for patients with schizophrenia and psychosis in Parkinson’s disease in four out of seven studies, except in treatment-resistant cases. There is a Grade B recommendation this diagnosis based on the levels of evidence. Nabiximols and CBD were beneficial in cannabis-related disorders in almost all studies with Grade B recommendation, resulting in a decreased risk of withdrawal symptoms and dependence among participants. The effect on cannabis-related craving was pronounced, with an additive benefit from the use of psychotherapeutic options such as MET or CBT. One open-label trial suggested favorable evidence for the use of cannabinoids CBD and Δ9-THC for hyperactivity, self-injurious behaviors, and anxiety symptoms in patients with ASD with Grade B recommendation. CBD was helpful in patients with anxiety and insomnia related to SAD and PTSD in one chart review. Nabiximols was found to be effective in reducing the frequency and severity of tics and improving the quality of life in patients with Tourette syndrome according to case reports. There was no firm evidence to support CBD to treat bipolar mania (one case report) or nabiximols (one RCT) to treat ADHD. There is Grade B (moderate) recommendation for attention deficit hyperactivity disorder. Grade C recommendation (weaker) exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These recommendations should be considered in the context of limited number of available studies. The authors recommend well-planned randomized controlled trials to further study the benefits of CBD and CBD-containing options such as nabiximols in patients with psychiatric disorders. It is also important to assess the individual pharmacodynamic and pharmacokinetic effects of CBD and Δ9-THC in different treatments.
Abbreviations
- 5-HT
- 5-hydroxytryptamine
- ADHD
- Attention deficit hyperactivity disorder
- ARCI
- Addiction Research Center Inventory
- ASD
- Autism spectrum disorder
- ASI
- Addiction Severity Index
- AST
- Attention Switching Task
- AUC
- Area Under Curve
- BACS
- Brief Assessment of Cognition in Schizophrenia
- BDI
- Beck Depression Inventory
- BDNF
- Brain-derived neurtrophic factor
- BPRS
- Brief Psychiatric Rating Scale
- BSS
- Bodily Symptoms Scale
- CAPE
- Community Assessment of Psychic Experiences-Positive Scale
- CB1 receptor
- Cannabinoid receptor 1
- CB2 receptor
- Cannabinoid receptor 2
- CBD
- Cannabidiol
- CBT
- Cognitive–behavioral therapy
- CCQ
- Cannabis Craving Questionnaire
- CGI
- Clinical Global Impression
- Cmax
- Maximum Serum Concentration
- CSF
- Cerebrospinal fluid
- CWS
- Cannabis Withdrawal Scale
- CYP
- Cytochrome P450
- DEQ
- Drug Effects Questionnaire
- EPS
- Extrapyramidal symptoms
- FTND
- Fagerstrom Test for Nicotine Dependence
- GAF
- Global Assessment of Functioning
- GI
- Gastrointestinal
- GPR
- G-protein-coupled receptor
- HAM-A
- Hamilton Anxiety Rating Scale
- HDRS
- Hamilton Rating Scale for Depression
- IQR
- Interquartile range
- MCCB
- MATRICS Consensus Cognitive Battery
- MCQ
- Marijuana Craving Questionnaire
- MCQ-SF
- Marijuana Craving Questionnaire-Short Form
- MET
- Motivational Enhancement Therapy
- Mini-SPIN
- Mini-Social Phobia Inventory
- MNWS
- Minnesota Nicotine Withdrawal Scale
- MWC
- Marijuana Withdrawal Symptom Checklist
- OCEBM
- Oxford Centre for Evidence-based Medicine – Levels of Evidence
- ORVRS
- Original Rush Videotape Rating Scale
- PANSS
- Positive and Negative Syndrome Scale
- PPQ
- Parkinson Psychosis Questionnaire
- PSQI
- Pittsburgh Sleep Quality Index
- PTSD
- Post-traumatic Stress Disorder
- QbTest
- Quantified Behavioral Test
- RAVLT
- Rey Auditory Verbal Learning Test
- RCT
- Randomized controlled trial
- SAD
- Social Anxiety Disorder
- SAFTEE
- Systematic Assessment for Treatment Emergent Events
- SANS
- Scale for the Assessment of Negative Symptoms
- SCARED
- Screen for Anxiety-related Disorders
- SCWT
- Stroop Color Word Test
- SDSC
- Sleep Disturbance Scale for Children,
- SMHSQ
- St Mary’s Hospital Sleep Questionnaire
- SOFAS
- Social and Occupational Functioning Assessment Scale
- SSPS
- Self-Statements During Public Speaking
- SSPS-N
- Negative Self-Statements
- STAI
- Spielberger State-Trait Anxiety Inventory
- THC
- Tetrahydrocannabinol
- THCCOOH
- 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol
- TLFB
- Timeline Follow-Back
- TRPV
- Transient receptor potential channels
- UDP-glucuronosyltransferases
- Uridine 5′-diphospho-glucuronosyltransferase
- USA
- United States of America
- VAMS
- Visual Analog Mood Scales
- WDS
- Withdrawal Discomfort Score
- YGTSS
- Yale Global Tic Severity Scale
- YMRS
- Young Mania Rating Scale
- Δ9-THC
- Δ9-tetrahydrocannabinol
Acknowledgements
The authors thank Erin Ellington (DNP, APRN, PMHNP-BC, Clinical Associate Professor, University of Missouri Kansas City, School of Nursing and Health Studies), who helped us improve the language of this article, and K. Shashok (AuthorAID in the Eastern Mediterranean), who provided additional editing of the revised manuscript.
Previous submissions
This article has not be presented or submitted previously.
Funding
None.
Availability of data and materials
Available to others on request.
Ethics approval and consent to participate
Not needed for this review.
Competing interests
The authors declare that they have no competing interests.