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The therapeutic role of Cannabidiol in mental health: a systematic review

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.

PRISMA Flow Diagram

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).

Table 1

Studies of CBD use in the treatment of schizophrenia and psychosis in Parkinson’s disease and levels of evidence (1 to 5)*

Schizophrenia CBD RCT Level 2 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.

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)

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).

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.

6–35 days = Participants were started on 40 mg twice a day, titrated to 1280 mg/day depending on efficacy and tolerability.

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.

4–30 days: CBD oil was increased to 1500 mg/day in divided doses.

After 35 days: Haloperidol was started.

– 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%).

– 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.

BACS: Brief Assessment of Cognition in Schizophrenia, BPRS: Brief Psychiatric Rating Scale, CBD: cannabidiol, CGI: Clinical Global Impressions, EPS: extrapyramidal symptoms, GAF: Global Assessment of Functioning, GI: Gastrointestinal, MCCB: MATRICS Consensus Cognitive Battery, PANSS: Positive and Negative Syndrome Scale, PPQ: Parkinson Psychosis Questionnaire, RCT: randomized controlled trial, SANS: Scale for the Assessment of Negative Symptoms, SCWT: Stroop Color Word Test, Δ9-THC: Δ9-tetrahydrocannabinol

*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)

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).

Cannabis-related disorders

The present review included three RCTs (107 patients), two open-label trials (28 patients), one case series of four patients, and two case reports for cannabis-related disorders as summarized in Table  2 (Solowij et al., 2018; Crippa et al., 2013; Trigo et al., 2016a; Trigo et al., 2018; Trigo et al., 2016b; Allsop et al., 2014; Pokorski et al., 2017; Shannon & Opila-Lehman, 2015). Of the eight studies, level 2 evidence was found in three RCTs, level 3 evidence in two clinical trial, and level 4 evidence in two case reports and one case series (OCEBM, 2019). For cannabis-related disorders, there is Grade B recommendation based on majority of studies ranked at the level 2 and level 3 of evidence.

Table 2

Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of cannabis-related disorders and levels of evidence (1–5)

6 days of nabiximols or placebo treatment, 3 days of washout, and 28-day follow-up period

Starting dose = 8 sprays, total dose of 21.6 mg THC and 20 mg CBD at 4 PM and 10 PM

Maximum dose = 8 sprays 4 times a day

– Nabiximols reduced CWS scores by 66% compared to 52% with placebo for duration for treatment (P = .01).

– It resulted in a decrease in appetite loss, decrease in cravings (p = 0.4), irritability and aggression (p = .o1).

– The time duration for cannabis withdrawal was 3.10 days with Nabiximols compared to 4.9 days with placebo (p = .04)

– The retention rate was 85% with medications compared to 50% with placebo.

The number and severity of adverse events did not differ significantly between groups.

Fixed dose = 4 sprays of medications every hour

Self-titrated dose: Patients were allowed to use 4 sprays as needed every hour. The maximum dose was 40 sprays/day.

– Medication intake was higher on fixed regimen as compared to self-titration conditions. There was significant differences between conditions (F(3,24) = 8.561, p < 0.001).

– Mean time for having feeling of “high” was clearly higher during SAU (6.6–7.3 h) compared with Sativex (2.4–3.3 h) or placebo (0.1–0.3 h), as self-reported by participants in their smoking diary (Fig.  1c )

– There were lesser withdrawal during self-titrated and fixed Sativex as compared to the corresponding placebo conditions (F(7,56) = 3.860, p < 0.01).

Nabiximols and weekly MET/CBT = 20

12 weeks 18–65 Nabiximols = 113.4 mg THC/105 mg CBD

BPRS, SAFTEE, HAM-A, HDRS, TLFB for cannabis, tobacco, caffeine

and alcohol, FTND, ASI, BDI, DEQ, Profile of Mood States, MWC, MCQ-SF, SMHSQ

– Nabiximols was well-tolerated with a dose range of 4.1 to 12.8 sprays/day.

– There was reduction in cannabis use in the nabiximols (70.5%) and placebo groups (42.6%).

– Five participants in the placebo group and four participants in the nabiximols group used other recreational drugs.

– High medication sub-group suggested a significant effect of time (F12,90.1 = 10.386, p < .001), no effects of treatment (F1,8.1 = 1.200, p = .305) but a significant time x treatment interaction.

CBD = 600–1200 mg/day in divided doses CWS, daily urine sample and blood samples on day 1, 3, and 7, THC COOH and CBD quantification

– For 600 mg/day of CBD: 2 out of 5 participants completed the 7-day inpatient treatment. These 2 participants reported abstinence at follow-up (day 28) and the 3 remaining participants reported decreased cannabis use, confirmed by blood and urine analysis.

– For 600 mg twice a day: of 3 participants, 2 reported abstinence and the 1 remaining one had decreased use of cannabis, confirmed by blood and urine analysis.

– All participants reported a decrease in CWS score.

– There was an improvement in severity of depression (p = 0.017), verbal learning, memory performance, and frequency of positive psychotic-like symptoms (p = 0.025) with decreased level of distress from baseline to endpoint.

– The state anxiety increased with no change in trait anxiety, functional impairment, and accuracy on cognitive tests.

CWC, CCQ, TLFB for cannabis, tobacco, caffeine and alcohol

– Reduction in cannabis intake from baseline to endpoint with no compensatory increase in use of other substances (F(18,54) = 4.663, p < 0.001).

– The craving scores increased initially during the first 2 weeks with a subsequent reduction in craving from week 9 (F(18,54) = 7.091, p < 0.001) .

– No significant difference in withdrawal scores for the duration of study (F(18,54) = 0.805, p value = non-significant)

The dose of CBD was 300 mg on day 1 and 600 mg on days 2–10.

600 mg was administered in divided doses.

– CBD resulted in faster, progressive relief from withdrawal, anxiety, and dissociative symptoms.

– Marijuana withdrawal symptom checklist had drop of baseline score of 12 to zero, from 5 to zero for Withdrawal discomfort scale.

– The scores for Beck Anxiety Inventory decreased from 6 to zero and 10 to zero for Beck Depression Inventory.

– At 6 month follow-up, return to cannabis use but at a lower rate.

Initial regimen: 24 mg CBD (6 sprays as needed during the day and 2 sprays at night).

The dose was decreased to 18 mg with 6 spray at night only.

Self-reported cannabis use, PSQI, HAM-A

– Patient was able to maintain abstinence from cannabis.

– Improvement in HAM-A score from 16 to 8 was reported, indicating mild anxiety.

– Patient had a regular sleep schedule and scores of 7 to eight were reported.

ARCI: Addiction Research Center Inventory, ASI: Addiction Severity Index, AST: Attention Switching Task, BDI: Beck Depression Inventory, BPRS: Brief Psychiatric Rating Scale, CAPE: Community Assessment of Psychic Experiences-Positive Scale, CBD: cannabidiol, CBT: cognitive–behavioral therapy, CCQ: Cannabis Craving Questionnaire, CWS: Cannabis Withdrawal Scale, DEQ: Drug Effects Questionnaire, FTND: Fagerstrom Test for Nicotine Dependence, GAF: Global Assessment of Functioning, HAM-A: Hamilton Anxiety Rating Scale, HDRS: Hamilton Rating Scale for Depression, MCQ: Marijuana Craving Questionnaire, MCQ-SF: Marijuana Craving Questionnaire-Short Form, MET: motivational enhancement therapy, MNWS: Minnesota Nicotine Withdrawal Scale, MWC: Marijuana Withdrawal Symptom Checklist, PSQI: Pittsburgh Sleep Quality Index, RAVLT: Rey Auditory Verbal Learning Test, SAFTEE: Systematic Assessment for Treatment Emergent Events, SOFAS: Social and Occupational Functioning Assessment Scale, SMHSQ: St Mary’s Hospital Sleep Questionnaire, STAI: Spielberger State-Trait Anxiety Inventory, TLFB: Timeline Follow-Back, WDS: Withdrawal Discomfort Score, THCCOOH: 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol, Δ9-THC: Δ9-tetrahydrocannabinol

“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)

Four of these studies evaluated the efficacy of nabiximols, and four others reported the use of CBD. The doses tested ranged from 20 mg CBD to a maximum of 1200 mg/day. Nabiximols was used in spray form at doses ranging from an average of 28.9 sprays/day (equivalent to 77.5 mg THC or 71.7 mg CBD) to 40 sprays/day (equivalent to 108 mg THC or 100 mg CBD). In CBD-only studies the dose of CBD ranged from 200 to 600 mg/day in divided doses. All three RCTs in this section provided evidence for the use of nabiximols for moderate to severe cannabis use disorder. These trials tested different doses of nabiximols ranging from 21.6 mg THC and 20 mg CBD (twice a day) to 113.4 mg THC or 105 mg CBD per day. All trials reported lower withdrawal rates, better tolerance, and retention rates in the experimental group. Moreover, no serious adverse effects were reported in any of these studies. In one RCT, nabiximols (total dose of 21.6 mg THC and 20 mg CBD at 4 and 10 in evening and night, respectively) was associated with marked improvement in cannabis withdrawal symptoms, leading to shorter withdrawal times and higher retention rates (Allsop et al., 2014). In a second RCT, a fixed dose of nabiximols produced more positive results compared to self-titrated administration (Trigo et al., 2016a). Patients in the fixed-dose group had four sprays of medications every hour compared to four sprays as needed every hour in self-titrated dose group. The maximum dose was 40 sprays/day in the self-titrated dose group. Medication intake was higher with fixed doses, which were associated with fewer withdrawal symptoms compared to the self-titrated regimen (Trigo et al., 2016a). In another RCT, the efficacy and safety of nabiximols were compared to a placebo while all participants also received weekly motivational enhancement therapy (MET) and cognitive–behavioral therapy (CBT) (Trigo et al., 2018). The dose range of 4.1 to 12.8 sprays/day was reported among nabiximols group. The withdrawal scores in this study were similar in both groups (Trigo et al., 2018). Only one of the studies reported decreased appetite, while the number and severity of adverse effects were not reported or observed in the other two RCTs.

Two open-label studies testing the effectiveness of two different concentrations of CBD (200 mg/day and 600–1200 mg/day) obtained positive outcomes with doses as low as 600 mg/day (Hallak et al., 2010; Pokorski et al., 2017). These studies had a small sample size of eight (Solowij et al., 2018) and 20 (Pokorski et al., 2017) participants, respectively. In the former open-label trial with eight participants, a dose of 600 mg/day was tested, and two out of five participants completed the 7-day inpatient treatment. These two participants reported abstinence at follow-up (day 28), and the remaining three participants reported decreased use of cannabis, confirmed by blood and urine analysis. In the second group, participants took 600 mg twice a day. Two out of three participants reported abstinence and in the remaining one, cannabis use had decreased, as confirmed by blood and urine analysis. All participants showed a decrease in Cannabis Withdrawal Scale scores. The second open-label trial tested the effectiveness of 200 mg CBD in divided doses in improving cognition and depressive symptomatology among patients with chronic cannabis use, and found improvement in severity of depression, verbal learning, and memory performance, and decreased frequency of positive psychotic-like symptoms and level of distress from baseline to endpoint (Solowij et al., 2018). State anxiety increased with no change in trait anxiety, functional impairment, or accuracy on cognitive tests (Solowij et al., 2018).

The remaining studies were either case series or case reports; all found positive outcomes in withdrawal and cannabis-dependence symptoms (Crippa et al., 2013; Trigo et al., 2016b; Shannon & Opila-Lehman, 2015). Mean age in the case series was 35 years, although the first participant was 19 years old and the second was 27 years old. The case series used self-titrated nabiximols at a dose of 77.5–113.4 mg THC and 71.5–105.0 mg CBD (Trigo et al., 2016b). Moreover, all participants reported a significant reduction in craving (Crippa et al., 2013; Trigo et al., 2016b; Shannon & Opila-Lehman, 2015), quicker relief (Crippa et al., 2013), lower anxiety, and an improved sleep schedule (Shannon & Opila-Lehman, 2015). However, the case series reported increased craving scores during the first 2 weeks with a subsequent reduction in craving at week 9. CBD was well-tolerated in this patient population, except for decreased appetite reported in one study (Trigo et al., 2016b). For patients receiving nabiximols or CBD, treatment should be augmented with psychotherapeutic modalities considering the positive evidence for an effect on cravings.

The effectiveness and tolerability of CBD and nabiximols for moderate to severe cannabis use disorder was reported in several studies. The efficacy may also be due to the synergetic or additive benefits of Δ9-THC and CBD rather than CBD alone. The Δ9-THC component of nabiximols decreases the severity of withdrawal symptoms, lowering the risk of relapse (Trigo et al., 2016a). However, there is mixed evidence for the role of nabiximols in cannabis-related craving (Trigo et al., 2016a; Trigo et al., 2018; Trigo et al., 2016b). Studies that included combined motivation enhancement and behavioral response prevention strategies suggested a reduction in craving (Trigo et al., 2016a; Trigo et al., 2018). CBD is thought to modulate the euphoric, anxiogenic, psychological, and physiological effects of Δ9-THC (Crippa et al., 2013). However, these benefits of CBD alone and in combination with THC need to be explored in head-to-head studies.

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.

Table 3

Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of other psychiatric disorders and levels of evidence (1–5)*

CBD for ADHD Symptom Relief

it’s no surprise that diagnoses of ADHD have increased 42% in eight years. Thankfully, the natural and therapeutic properties of cannabidiol, better known as CBD, are proving to be an effective option in bringing focus and relief to the ADHD-ridden mind. (1)

While studies are still in the early phases, understanding the link between CBD and ADHD doesn’t have to be overly complex. Let’s dive in and keep it simple.

What Is ADHD?

ADHD (Attention Deficit Hyperactivity Disorder) is often thought of as a childhood disease, however, 4% of US adults also suffer daily symptoms. (2)

Regardless of whether hyperactivity is present or not, ADHD often affects school-aged children and is the most commonly diagnosed neurodevelopmental disorder for children. (3)

Sufferers of ADHD must learn to adapt to difficulties in paying attention, remembering seemingly simple tasks, being over-compulsive and more. This often leads to difficulties in school, at work, and in relationships.

Currently, managing ADHD requires a combination of medications and behavioral therapy. A 2012 study estimated that caring for ADHD can cost up to $2,000 for children and over $4,000 for adults every year. (4)

These costs add up. Medication, tutoring, therapy, and specialists can all be a part of a standard treatment plan. The FDA has approved numerous medications to treat ADHD; however, everyone responds to medication differently and it can be a challenge to find what works best.

Furthermore, many medications have side effects including:

  • Sleepiness
  • Loss of appetite
  • Increased moodiness and irritability
  • Headaches
  • Tics
  • …and more.

How Does CBD Counteract ADHD?

CBD naturally restores homeostasis to the body, bringing balance to the areas that may need a little more support.

Although it won’t cure ADHD, CBD could provide relief and focus for a few hours at a time, depending on usage and dosage. When used consistently, it can decrease the negative symptoms of ADHD and increase concentration in sufferers.

Additionally, ADHD side effects can include anxiety, paranoia, and depression. Studies show CBD can counteract each of these by targeting the endocannabinoid system – a key player in regulating the body’s hormones and responding to imbalances. (6)

Similar to any other medication, CBD may need to be used indefinitely. However, because cannabidiol is not addictive and has nearly no side effects, it may be one of the least harmful ways to treat the symptoms of ADHD. Consumption can be stopped at any point without any ill effects besides a return of symptoms.

CBD can be used in a number of ways including topical creams, oils, edibles, and inhalants. However, some methods take longer for the body to process or are less subtle than others. Administering a few drops under the tongue or inhaling via a vape are the easiest ways for CBD oil to be absorbed through the bloodstream and begin affecting the brain and nervous system.

What Is CBD?

While researchers explore better ways to treat ADHD, one new option is proving to be effective in the management of the condition: CBD.

CBD, like THC, is one of many chemical substances known as cannabinoids found in the cannabis plant. Unlike THC, CBD does not produce psychoactive effects – it cannot get you “high”. (5)

It does, however, have many natural properties with countless health benefits. CBD is a natural anti-inflammatory and antioxidant. It’s also full of Omega 3s and Omega 6s, two fatty acids essential to brain health.

By targeting specific neurotransmitters, CB1 and CB2 receptors, CBD can reduce anxiety and increase the ability to focus. While research is still in the early phases, it may be beneficial to add CBD to a daily routine for those who suffer from ADHD and are frustrated with traditional treatment options.