Psychiatric Annals

CME Article 

A Critical Systematic Review of Evidence for Cannabinoids in the Treatment of Schizophrenia

Anoop Sankaranarayanan, MD, MHM, FRANZCP; Helen Wilding, GradDipInfoMgt; Erica Neill, BBSc (Hons), MBSc, PhD; David Castle, MD, FRCPsych, FRANZCP

Abstract

Cannabinoids have an emerging evidence base as an effective treatment option in a number of medical conditions, including anorexia and intractable vomiting. It is well known that patients with schizophrenia are more likely to use cannabis; it has also been argued that this could be a way of self-treating adverse side effects (secondary to antipsychotics) in a group of people with schizophrenia. Therefore, studies have attempted to examine the use of cannabinoids in schizophrenia. Given the recent interest in the use of cannabinoids in general and the ensuing ethical debates, we systematically review the available literature on the use of four cannabinoids, namely delta-9-tetrahydrocannabinol, dronabinol, rimonabant, and cannabidiol, in the management of schizophrenia. We also offer suggestions for future research in this area. [Psychiatr Ann. 2018;48(5):214–223.]

Abstract

Cannabinoids have an emerging evidence base as an effective treatment option in a number of medical conditions, including anorexia and intractable vomiting. It is well known that patients with schizophrenia are more likely to use cannabis; it has also been argued that this could be a way of self-treating adverse side effects (secondary to antipsychotics) in a group of people with schizophrenia. Therefore, studies have attempted to examine the use of cannabinoids in schizophrenia. Given the recent interest in the use of cannabinoids in general and the ensuing ethical debates, we systematically review the available literature on the use of four cannabinoids, namely delta-9-tetrahydrocannabinol, dronabinol, rimonabant, and cannabidiol, in the management of schizophrenia. We also offer suggestions for future research in this area. [Psychiatr Ann. 2018;48(5):214–223.]

Cannabis is the most commonly abused illicit drug in the world with some 147 million people, or 2.5% of the world's population, reportedly using it.1 Furthermore, some 13.1 million people meet criteria for cannabis dependence.2 People diagnosed with schizophrenia are more likely to use cannabis; reported rates for use among schizophrenia patients range from 17% to 80%.3 A large epidemiological study from Australia reported higher rates, with 97% of people with schizophrenia reporting lifetime prevalence and 49% stating they had used it in the past year.4

A recent meta-analysis on the use of cannabis among patients with first-episode psychosis estimated that 33.7% of participants used cannabis at the time of their first episode of psychosis.5

Despite the prevalence of cannabis use, it is illegal in many countries due to concerns about its impact on health. Short-term effects include impairments in cognition and motor function along with transient psychotic symptoms. Long-term use can lead to addiction, permanent cognitive impairment (particularly if use began in early adolescence), chronic bronchitis, and reduced quality of life;6 it can also be a cumulative causal factor for schizophrenia.7

Despite these concerns, the arguments for and against the legalization of cannabis rage on, with advocates for legalization citing the importance of personal choice, taxation benefits, increased ease of access for medical use, and decreased illegal activity.6 At the center of this debate is the discussion of the complex relationship between cannabis use and schizophrenia. For example, two meta-analyses indicate that cannabis may increase (by nearly 4-fold) the risk of schizophrenia or psychosis,7 and that this risk is dose-dependent.8 Furthermore, research shows that cannabis meets many of Hill's criteria for causation in relation to the development of schizophrenia. These include (1) use preceding illness onset, (2) biological gradient (greater exposure leading to greater incidence), (3) biological plausibility (interaction between cannabis and dopamine activity), (4) experimental evidence (cannabis inducing psychosis symptoms), (5) consistency (increased risk of psychosis among heavy users), and (6) coherence (consistency between laboratory and epidemiological findings).9

Countering this causative argument is information gathered from self-report studies that suggest people with schizophrenia use substances such as cannabis to self-medicate negative symptoms, depression, side effects of antipsychotics, and for positive affect (to relieve boredom, to provide stimulation, to feel good, to get high, or to relax and socialize with peers).10–13 Although self-report studies have intrinsic methodological issues and may be biased, other research confirms that cannabis-using patients with schizophrenia have superior cognitive functioning14 and better cardiometabolic profile.15 Similar findings of better metabolic indices have also been reported among cannabis users in the general population.16,17

Furthermore, there is also a significant body of literature that demonstrates the potential treatment options for cannabis in patients with schizophrenia. The varied effects of cannabis can, in part, be attributed to different compounds within the plant, which include a number of related compounds known as cannabinoids. To date, only a small number of these have been investigated in detail.18 Four of these compounds are examined in this review, including delta-9-tetrahydrocannabinol (THC), dronabinol, rimonabant, and cannabidiol (CBD).

THC is responsible for the psychoactive effects of cannabis, and it is this compound that has been implicated in the development and exacerbation of psychosis.9,19 CBD, on the other hand, has an opposing profile with evidence demonstrating that it has antipsychotic properties.20,21 Furthermore, it has been shown to ameliorate the cognitive effects of THC.22 Although CBD has only recently come to light in the media, the first study finding that CBD has antipsychotic effects was published in 1982.23 Research since that time has demonstrated that CBD can provide symptom relief for a wide range of illnesses, including psychosis.24 In addition to educating us on the potential benefits of CBD, these many years of research have also demonstrated that CBD has an excellent safety profile with low toxicity21 and few side effects.25

Dronabinol, a cannabinoid 1 (CB1) receptor partial agonist, has been used to reduce nausea in chemotherapy,26 treat appetite loss associated with anorexia27 and AIDS,28 and has also been used to treat sleep apnea29 and pain.30 In addition, there is a small body of research demonstrating that dronabinol can ameliorate psychosis in treatment-resistant schizophrenia.31,32 Rimonabant (a CB1 receptor antagonist/inverse agonist) has been trialed for use in smoking cessation33 and weight loss,34 with three studies specifically exploring its efficacy in schizophrenia,31–33 with mixed results and serious concerns regarding side effects.

Considering that available antipsychotics often provide only modest improvement in functioning and symptom resolution in patients with schizophrenia,35,36 and the fact that medical marijuana has found its way into the arena of mental disorders, we review here the current evidence for the use of cannabinoid agents in the treatment of schizophrenia.

Methodology

The review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.37

Search Strategy

Studies were identified by systematically searching nine bibliographic databases and checking reference lists of relevant articles. Search strategies were developed and run by an experienced medical research librarian (H.W.) in consultation with D.C. and A.S.

An initial search strategy using a combination of MeSH (Medical Subject Heading) terms and text words was applied to Ovid MEDLINE (including epub ahead of print, in-process & other non-indexed citations). The search strategy was then adapted as appropriate for other databases, taking into account different subject headings and syntax. Other databases searched were Embase ( Embase.com), Emcare (Ovid), PsycINFO (Ovid), CINAHL (EBSCOhost), Cochrane Library, Proquest Nursing, Informit Health Collection, and Clinicaltrials.gov. Results were limited to English language but not by date. Searches were last updated on February 10, 2017. Figure 1 shows the MEDLINE search strategy.

Medline search strategy used in this review.

Figure 1.

Medline search strategy used in this review.

All potentially eligible studies were considered for review. Duplicates were removed by H.W. and records imported into Covidence software (Cochrane; London, UK) for screening. Two independent reviewers (A.S. and H.W.) screened articles on title and abstract, and then full text, according to agreed inclusion and exclusion criteria. In the event of a conflict, D.C. had the deciding vote.

Inclusion criteria are listed in Table 1. Exclusion criteria are listed in Table 2.

Inclusion Criteria for Studies

Table 1:

Inclusion Criteria for Studies

Exclusion Criteria for Studies

Table 2:

Exclusion Criteria for Studies

Quality Ratings

As the studies were clinical trials, a checklist was developed based on the Consolidated Standards of Reporting Trials (CONSORT) statement38 for randomized controlled trials and the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND),39 which gave a maximum of 20 points. The quality checklist is available as Table 3. Levels of evidence were further characterized individually based on Sackett's rules of evidence.40 Higher scores indicate a better quality of evidence.

Checklist to Assess Quality of Included Studies

Table 3:

Checklist to Assess Quality of Included Studies

Results

Figure 2 shows the PRISMA flow-diagram for the stages of systematic review. There were 3,106 search results retrieved and 2 additional records identified from reference lists; 2,089 articles remained after duplicates were removed. A.S. and H.W. screened the 2,089 records against title and abstract and then assessed 139 full-text articles for eligibility. Data extraction from the nine included studies was carried out by A.S. and checked by D.C.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram: therapeutic cannabinoids in psychosis. Reprinted with permission of the Creative Commons Attribution License from Moher et al.37

Figure 2.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram: therapeutic cannabinoids in psychosis. Reprinted with permission of the Creative Commons Attribution License from Moher et al.37

Our final selection included nine studies, with a total of 118 participants. Of these studies, three explored the use of rimonabant q135;41,42 three explored CBD,43–45 one explored delta-9 THC,46 and two explored dronabinol or synthetic tetrahydrocannabinol31,32 in people with schizophrenia (Table 4).

Summary of Included Studies

Table 4:

Summary of Included Studies

Six of the included studies had a double-blind design,41,42,44–46 two were case series,31,32 and one was a crossover trial.43 Only two of the double-blind studies35,45 provided level I evidence; this was because these studies had either reported a sample-size calculation and/or had sufficient sample based on Nunnally's principle47 (Table 5).

Quality of Included Studies

Table 5:

Quality of Included Studies

Although most of the included studies had small sample sizes, five were of good quality, scoring 15 or higher on the 20-point quality scale,35,41,42,45,46 with the study of Leweke et al.45 scoring highest on the quality assessment. The double-blind studies generally scored higher than the other studies by virtue of the study design; however, Hallak et al.44 was a poorly reported study despite being a double-blind trial. The case series scored low on quality assessment.31,32 Interestingly, the majority of the double-blind trials42,44,46 were negative.

CB1 and CB2 Agonists

CB1 receptors are highly expressed in the brain regions associated with schizophrenia, including the cerebral cortex, basal ganglia, hippocampus, anterior cingulate cortex, and cerebellum, where they modulate presynaptic glutamate and gamma-aminobutyric acid (GABA) release. Three studies explored the use of delta-9-THC46 or dronabinol31,32 in people with psychotic disorders. D'Souza et al.,46 using a double-blind design, studied the acute effects of 2.5 or 5 mg of delta-9-THC given intravenously in two doses 3 weeks apart. They compared 13 stable patients with schizophrenia treated with antipsychotics with 22 healthy subjects. They measured cognitive, behavioral, motor, and neurochemical indices and found that delta-9-THC worsened positive, negative, and cognitive deficits and medication side effects.

On the other hand, Schwarcz et al.31,32 demonstrated that the synthetic delta-9-THC agent, dronabinol, improved functioning and well-being in patients with treatment-resistant schizophrenia. They described improvement in 4 of 6 treatment-resistant patients in the first study,31 and described four improvements in Clinical Global Impression scores in four additional patients with chronic treatment-refractory schizophrenia in the second study;32 their behaviors, however, deteriorated when the dronabinol was phased out. Of note, they included people with a past history of “response” to THC. For this reason, a major limitation of these studies is selection bias (ie, specifically selecting patients with a history of calming effect with marijuana increases the likelihood of a positive response.)

In summary, these results indicate that dronabinol may have a role in improving function in a small group of people with schizophrenia, particularly in those with a history of cannabis use without worsening in the symptom profile while using the substance. However, the level of evidence is low (level V) and needs to be considered in the light of overwhelming data showing that most people with schizophrenia who use THC have a worsening of psychotic symptoms.48

Rimonabant

Rimonabant is a CB1 receptor antagonist/inverse agonist. CB1 antagonists can potentially enhance cognition in people with schizophrenia by influencing prefrontal GABAergic tone. Alternatively, they can enhance striatal dopamine release and affect reward-seeking behaviors. Three studies have explored the effects of rimonabant in schizophrenia. Meltzer et al.35 conducted a novel meta-trial design for efficient, simultaneous initial evaluation of the therapeutic potential of four compounds (neurokinin [NK3] antagonist; serotonin 2A/2C antagonist; CB1 antagonist; and neurotensin [NTS1] antagonist). An unbalanced random assignment method (placebo [n = 98]; NK3 antagonist [n = 70]; serotonin 2A/2C antagonist [n = 74]; CB1 antagonist [n = 72]; NTS1 antagonist [n = 69]; and haloperidol [HPL; n = 98]) was used, and data from the groups receiving placebo and HPL from each of the studies were pooled and used to compare the efficacy and safety of each investigational drug. This allowed the use of a smaller total number of randomly assigned comparison patients, and the authors studied the effects on psychopathology and scores of motor side effects. This study failed to demonstrate that rimonabant had any superior efficacy compared to placebo.

Kelly et al.41 specifically explored the effects of rimonabant in obese patients with schizophrenia (rimonabant n = 7; placebo n = 8) who were otherwise well-stabilized on second-generation antipsychotics. The main focus was the effect of rimonabant on obesity and metabolic indices. Interestingly, rimonabant improved Brief Psychiatric Rating Scale total score and anxiety/depression and hostility factors significantly, but it had limited effect on weight or metabolic measures or depression. The study was limited by small sample size and premature termination. Reported adverse effects associated with rimonabant included headache, enuresis, anorexia, sedation, abdominal pain, weight loss, malaise, tinnitus, nausea, dizziness, dry mouth, insomnia, and vomiting.

In a further study of rimonabant, Boggs et al.42 focused on the neurocognitive effects in stable obese patients (rimonabant n = 8; placebo n = 9) with schizophrenia. People taking rimonabant improved on scores of reinforcement learning, especially to positive reinforcement. It was hypothesized that modulation of striatal dopamine release and subsequent increase in D1 dopamine receptor transmission mediated this improvement. Once again, small sample size and premature termination limit the interpretability of results.

Taken together, rimonabant has provided mixed results in people with schizophrenia. Whereas a well-powered, double-blind trial failed to demonstrate any efficacy, a smaller and shorter trial found that rimonabant both reduced psychopathology scores and improved cognition in patients with schizophrenia. In any event, the compound has been withdrawn worldwide due to concerns related to depressive side effects, but similar compounds might have a future role in schizophrenia therapies.

Cannabidiol

Cannabidiol is a non-psychotomimetic component of the cannabis plant that binds to CB1 receptors and also inhibits the enzyme fatty acid amide hydrolase (FAAH) that catalyzes anadamide degradation.

We identified three studies that explored CBD in schizophrenia. Zuardi et al.43 conducted an open trial in three patients with treatment-resistant schizophrenia; they found that symptoms improved in one patient. Doses used ranged from 40 to 1,280 mg/day.

A double-blind trial by Hallak et al.44 compared acute administration of different doses of CBD (300 and 600 mg) to placebo on selective attention and psychotic symptoms in 28 patients with schizophrenia. Patients who received either placebo or 300 mg of CBD performed better than those who received 600 mg of CBD. CBD did not have a demonstrable effect on psychotic symptomatology.

Finally, Leweke et al.45 performed a double blind, single-center, parallel group, randomized controlled trial comparing cannabidiol to amisulpride in 42 patients with schizophrenia or schizoaffective disorder over a 4-week period. They found that both agents (up to 800 mg/day) reduced psychotic symptoms; however, CBD was associated with lower incidence of extra-pyramidal side effects, weight gain, and prolactin increase. Anandamide levels were associated with treatment response in those using cannabidiol but not amisulpride.

Considering that the study by Leweke et al.45 was double-blind, this indicates level I evidence for efficacy of CBD in reducing psychotic symptoms in schizophrenia; the results of the open trial and the second double-blind trial are not as promising.43,44

Conclusions

Schizophrenia is complex and intriguing, but the association between cannabis use and schizophrenia is increasingly becoming more understood. Observational studies have shown that cannabis-using patients with schizophrenia have superior cognitive functioning14 and better cardio-metabolic profile.15

Our review suggests that cannabinoids have a role in treating schizophrenia. The level of evidence varies considerably depending on the agent studied and appears to be strongest for cannabidiol. It is also the best tolerated. However, the evidence is not homogeneous and was further limited because of small sample sizes. Sufficiently powered and rigorously conducted randomized controlled trials are required before definitive conclusions can be drawn.

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Inclusion Criteria for Studies

Clinical trials Conducted with adults (age 18 years and older) Diagnosis of schizophrenia, psychosis, early psychosis, or first episode psychosis Compared/used a therapeutic use of cannabinoids, synthetic cannabinoids, or combination of cannabinoids Described outcome measures in <list-item>

■ Positive, negative, or cognitive symptoms, and/or

</list-item><list-item>

■ Quality of life, and/or

</list-item><list-item>

■ Functional outcomes

</list-item>

Exclusion Criteria for Studies

Duplicate records Authors not identified Conference proceedings Animal studies Participants did not have schizophrenia or psychosis Inappropriate outcome measures Review or opinion papers Not clinical trial of cannabinoids or synthetic cannabinoids Case report

Checklist to Assess Quality of Included Studies

Topic Checklist Item Score
Title and abstract Identifies type of study 1

Introduction Provides scientific rationale 1

Objectives and hypothesis Clearly described 1

Type of study If randomized controlled trial 1

Participants Eligibility criteria (inclusion and exclusion) provided 1

Intervention Describes what was given
Setting and location
Duration and exposure 1

Randomization Describes how randomization was done 1

Blinding Describes blinding process (whether done and whether single or double) 1

Outcome Clearly described primary and secondary outcome measures 1

Analysis Sample size or power calculation 1
Describes smallest unit of analysis 1
Describes (at a minimum) analysis for primary and secondary outcomes, additional analysis, missing data, and statistical program 1

Results Participant flow 1
Baseline data (at a minimum): comparison of study and control population, those lost to follow-up, numbers analyzed, and intention to treat 1

Outcomes For each primary and secondary outcome 1
Ancillary results 1
Harm or adverse events 1

Discussion Interpretation 1
Limitations and source or bias 1
Generalizability 1

Summary of Included Studies

Agent Study, Year Aim Design Participants Results
Cannabidiol Zuardi et al.,23 2006 To study effectiveness of CBD in treatment-resistant schizophrenia Crossover study 3 inpatients with DSM-IV schizophrenia Improvement in symptoms in one of three patients taking 1,280 mg
Hallak et al.,44 2010 Effects of acute CBD on selective attention using Stroop CWT Double blind 28 outpatients with schizophrenia No difference between placebo and CBD (300 mg) on CWT
Leweke et al.,45 2012 Compare CBD versus amisulpride Double blind 42 inpatients who were acutely psychotic with DSM-IV schizophrenia Improvement in symptomatology with both CBD (800 mg) and amisulpride (800 mg); fewer side effects with CBD
Delta-9 THC D'Souza et al.,46 2005 Study dose-related effects of delta-9-THC in patients with schizophrenia compared to healthy controls Double-blind parallel group 13 stable patients with schizophrenia and 22 healthy controls Delta-9-THC transiently worsened core psychotic and cognitive deficits
Synthetic delta-9-THC or dronabinol Schwarcz et al.,31 2009 Dronabinol in patients with refractory, chronic schizophrenia Case series 6 patients with DSM-IV schizophrenia 4 of 6 patients reported improvement with 3 reporting reduction in psychotic symptoms
Schwarcz and Karajgi,32 2010 Dronabinol in patients with refractory, chronic schizophrenia Case series 4 patients with DSM-IV schizophrenia 4 patients showed a reduction in CGI severity with 5–10 mg of BD twice daily
Rimonobant Meltzer et al,35 2004 Efficacy of rimonbant alongside other potential new antipsychotics Double blind 72 of 481 participants with DSM-IV schizophrenia received rimonobant No difference to placebo on any outcome measure
Kelly et al.,41 2011 Safety, tolerability, and effects on psychiatric symptoms in stable obese patients Double blind 15 clinically stable, obese participants with DSM-IV schizophrenia or schizoaffective disorder Rimonobant was associated with greater reduction in BPRS total, depression, and hostility scores and was well tolerated with no effects on weight or metabolic indices
Boggs et al.,42 2012 Effects of rimonobant for neurocognitive impairments Double blind 14 clinically stable, obese patients with DSM-IV schizophrenia or schizoaffective disorder who completed the trial Rimonobant did not improve global cognitive functioning but did improve specific learning deficit

Quality of Included Studies

Study, Year Design Level of Evidence Quality Score (Total 20) Comments
Boggs et al.,42 2012 Double blind II 15 Negative study; data from Kelly et al.41 to describe cognitive effects of rimonobant; rimonobant group had higher SANS score and were more likely to be taking clozapine and two SGA combinations, although this was not statistically significant. Small sample size and premature termination limit generalizability of findings
D'Souza et al.,46 2005 Double blind II 17 Negative study; aimed to study acute effect of intravenous delta-9-THC
Hallak et al.,44 2010 Double blind II 11 Negative study; studied acute effect of CBD on selective attention. Cannot rule out effects of chronic administration
Kelly et al.,41 2011 Double blind II 17 Positive study; however, small sample size and premature termination of study limit the quality of study
Leweke et al.,45 2012 Double blind I 20 Positive study; clear inclusion and exclusion criteria and employed modified intention-to-treat analyses
Meltzer et al.,35 2004 Double blind I 15 Negative study; meta-trial comparing multiple agents
Schwarcz et al.,31 2009 Case series V 9 Positive study; studied dronabinol in patients with treatment-resistant schizophrenia and demonstrated pre- and posttreatment differences in 4 of 6 patients; self-selection bias
Schwarcz and Karajgi,32 2010 Case series V 6 Positive study; described results for 4 of 8 patients; used subjective measures and did not report on nonresponders, excepting that there was no worsening
Zuardi et al.,43 2006 Crossover study V 12 1 of 3 patients with TRS responded; short course; funded by pharmaceutical company
Authors

Anoop Sankaranarayanan, MD, MHM, FRANZCP, is an Associate Professor (Conjoint), Western Sydney University; and a Visiting Medical Officer, St. John of God Hospital. Helen Wilding, GradDipInfoMgt, is a Senior Research Librarian, Carl de Gruchy Library, St. Vincent's Hospital; and a Senior Research Librarian, St. Vincent's Mental Health Service, St. Vincent's Hospital. Erica Neill, BBSc (Hons), MBSc, PhD, is a Research Fellow, Department of Psychiatry, Faculty of Medicine, University of Melbourne. David Castle, MD, FRCPsych, FRANZCP, is a Consulting Psychiatrist, St. Vincent's Hospital; and a Professor of Psychiatry, Faculty of Medicine, University of Melbourne.

Address correspondence to Anoop Sankaranarayanan, MD, MHM, FRANZCP, VMO Psychiatrist, St. John of God Hospital, 177 Grose Vale Road, North Richmond, NSW 2753, Australia; email: anoopshank2000@gmail.com.

Disclaimer: David Castle does not knowingly own any stocks or shares in any pharmaceutical company.

Disclosure: David Castle has received grant funding for research from Eli Lilly, Janssen Cilag, Roche, Allergen, Bristol-Myers Squibb, Pfizer, Lundbeck, AstraZeneca, and Hospira; travel support and honoraria for talks and consultancy from Eli Lilly, Bristol-Myers Squibb, AstraZeneca, Lundbeck, Janssen Cilag, Pfizer, Organon, Sanofi-Aventis, Wyeth, Hospira, and Servier; and is a current Advisory Board Member for Lundbeck, Shire, Pfizer, Servier, and LivaNova. The remaining authors have no relevant financial relationships to disclose.

10.3928/00485713-20180409-01

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