What do Cochrane systematic reviews say about the use of cannabinoids in clinical practice?

ABSTRACT BACKGROUND: The therapeutic effects of cannabinoid compounds have been the center of many investigations. This study provides a synthesis on all Cochrane systematic reviews (SRs) that assessed the use of cannabinoids as a therapeutic approach. DESIGN AND SETTING: Review of SRs, conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP). METHODS: A broad search was conducted in the Cochrane Database of Systematic Reviews to retrieve any Cochrane SRs that assessed the efficacy and safety of cannabinoids as a therapeutic approach. The results and key characteristics of all reviews included were summarized and discussed. RESULTS: Eight SRs were included. They assessed the use of cannabinoids for the following types of conditions: neurological (two SRs), psychiatric (two SRs), rheumatological (one SR), infectious (one SR) and oncological (two SRs). There was moderate-quality evidence showing that the use of cannabinoids reduced nausea and vomiting among adults, compared with placebo. Additionally, there was moderate-quality evidence showing that there was no difference between cannabinoids and prochlorperazine regarding the number of participants who reported vomiting, in this same population. CONCLUSIONS: This review identified eight Cochrane systematic reviews that provided evidence of unknown to moderate quality regarding the use of cannabinoids as a therapeutic intervention. Further studies are still imperative for solid conclusions to be reached regarding practical recommendations.


INTRODUCTION
More than 500 natural compounds (including cannabinoids, terpenoids and alkaloids) have been identified in the cannabis plant. The recreational and therapeutic effects of cannabinoid compounds (there are nearly 100 of these compounds) have been the center of many investigations. The most common constituent of cannabis is delta-9 tetrahydrocannabinol (THC), the substance that is considered to be the primary psychoactive agent in cannabis. 1 However, it has been hypothesized that not only THC but also a huge number of other cannabinoids (including synthetic analogues) such as cannabidiol, cannabinol, nabilone, dronabinol and levonantradol have therapeutic effects. The route of administration may play an important role in the effect that cannabis has, and this needs to be considered in designing health interventions. These possible routes involve smoking, vaporization, oral ingestion, passive exposure, intravenous injection and administration of rectal suppositories. 2 In 2018, a committee designated by the National Academies of Sciences, Engineering and Medicine (NASEM) of the United States described the following as health-related endpoints from medical use of cannabis: therapeutic effects; mental health effects; cannabis abuse; problems relating to cannabis use; cardiometabolic risks; incidence of cancer; and death. 3 A quick search for cannabis-related trials in the ClinicalTrials database (available at clinicaltrials.gov) in July 2018 showed that 432 studies are currently registered as trials in this database alone.
Most of these are investigating the use of cannabis as an intervention for a variety of conditions, such as anxiety, pain, nausea and vomiting, depression and attention-deficit hyperactivity disorder. 4 Despite the high amounts that have been invested in research on this topic, the relevance of cannabinoids as a therapeutic approach is still a matter of debate. Because these compounds may form a reasonable alternative for treating numerous conditions, it is imperative to assess the efficacy and safety of cannabinoids through well-designed and well-conducted randomized controlled trials.

OBJECTIVE
To present the evidence from Cochrane systematic reviews that assessed the therapeutic use of cannabinoids for any disease or condition.

Design
This was a review of Cochrane systematic reviews.

Setting
This review was conducted within the Discipline of Evidence-Based Medicine of Escola Paulista de Medicina (EPM), Federal University of São Paulo (Universidade Federal de São Paulo, UNIFESP).

Types of studies
We included the latest version of full Cochrane systematic reviews (SR). We did not consider protocols or any SRs that had the status "withdrawn" in the Cochrane Database of Systematic Reviews (CDSR).

Types of participants
We considered participants with any clinical condition, regardless of age or sex.

Types of intervention
We considered any intervention derived from cannabis and its synthetic analogues. The cannabinoid compounds considered in these reviews included cannabidiol, cannabinol, nabilone, dronabinol, levonantradol and delta-9-tetrahydrocannabinol (THC), in any regimens or doses, when used for therapeutic purposes. We considered any pharmacological or non-pharmacological intervention as comparators.

Types of outcomes
We considered any clinical, social, laboratory or economic outcomes, as assessed and reported in the systematic reviews included.

Search for reviews
We conducted a broad systematic search in the Cochrane Database of Systematic Reviews (via Wiley) on July 10, 2018. The search strategy is shown in full in Table 1.

Selection of systematic reviews
Two researchers (RLP and COCL) independently read all the abstracts that were retrieved, to check their eligibility in relation to the inclusion criteria. Any disagreements during the selection phase were resolved by a third author (RR).

Presentation of the results
We produced a synthesis of the key results and characteristics of all the reviews included, using a narrative approach (qualitative synthesis).
For each SR included, we identified the respective population, intervention, comparator and outcomes (PICO); methods for searching for and selecting studies; methods for and results from critical assessment; methods for pooling results (meta-analytic approaches); quality of the body of evidence for each outcome; and applicability. In situations in which multiple interventions were addressed by a single SR, we considered only those that were relevant for the present study.
NA RCT = randomized clinical trial; *GRADE (Grading of Recommendations Assessment, Development and Evaluation) aims to assess the quality of the body of evidence. Outcomes are assessed as presenting high quality of evidence (high confidence in results, i.e. the estimated effect is close to the true effect), moderate quality of evidence (it is very likely that the estimated effect is close to the real effect but there is possibility that it is not), low quality of evidence (confidence in the effect estimate is limited) or very low quality of evidence (the true effect is likely to be substantially different from the estimate effect).

Results from systematic reviews
The SRs addressed the following types of conditions: neurological (n = 2), 6,7 psychiatric (n = 2), 5,9 rheumatological (n = 1), 12 infectious (n = 1) 8 and oncological (n = 2). 10,11 The main findings from the SRs included and the quality of the evidence (using the GRADE approach) are shown in Table 2. A brief summary of each SR is presented below.

Dementia
There is some evidence that the cannabinoid system may play a role during the regulation of neurodegenerative processes, including in relation to excessive glutamate production, oxidative stress and neuroinflammation. Neurodegeneration is a feature common to various types of dementia. These findings have led to interest in whether cannabinoids might be useful for treating dementia. • Pain reduction: greater with nabilone than with placebo; no difference between nabilone and amitriptyline.
• Quality of life: better with nabilone than with placebo; no difference between nabilone and amitriptyline.
• Fatigue and depression: no difference between nabilone and placebo.
• Sleep pattern: greater improvement with nabilone than with amitriptyline.
• Mood: no difference between nabilone and amitriptyline.
• Withdrawal due to adverse events: higher in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group).
Comparisons with metoclopramide, domperidone and chlorpromazine showed weaker evidence, based on fewer trials and participants, for higher incidence of dizziness with cannabinoids.
Two RCTs (141 participants) compared an antiemetic drug alone with cannabinoid added to the antiemetic drug and did not show any differences between the groups.
It was concluded that cannabis-based interventions might be useful for adults with refractory chemotherapy-induced nausea and vomiting. However, the methodological limitations of the RCTs reduced the confidence regarding these findings. Future research considering the current chemotherapy regimens and newer antiemetic drugs is likely to modify these conclusions. For further details, refer to the original abstract, available from: http://cochranelibrary-wiley. com/doi/10.1002/14651858.CD009464.pub2/full.

Nausea and vomiting relating to chemotherapy among children
This review 10

DISCUSSION
This review included eight systematic reviews (SRs) that assessed the use of cannabinoids for neurological, psychiatric, rheumatological, infectious and oncological conditions. Only two of the SRs included assessed the overall quality of the evidence through using the GRADE approach. The only moderate-quality evidence found was related to the use of cannabinoids to treat chemotherapy-related nauseas and vomiting among adults, showing that the use of cannabidiol reduces nausea and vomiting among adults, in comparison with placebo. Additionally, there was moderatequality evidence showing that there was no difference between cannabinoid and prochlorperazine regarding the number of participants who reported vomiting. All other evidence ranged in quality from low to very low. These findings were similar to those of a previous overview of SRs that addressed only the effects of cannabinoids for nausea and vomiting related to chemotherapy. 13 The benefits and harm of any therapeutic intervention, including use of cannabinoids, need to be properly addressed through randomized controlled trials (RCTs). Thus, the scope of this review did not extend to presenting results from primary observational or animal experimentation studies. The results from such studies are more susceptible to bias and should always be taken to be exploratory. These studies may nevertheless be useful for guiding well-designed RCTs.
Regarding the implications for practice and research, the results presented in Table 2 may provide guidance for therapeutic proposals. However, it is important to emphasize that, because of the low quality of the evidence, further well-conducted RCTs may change the conclusions regarding the effects of the interventions.
According to these Cochrane SRs, use of cannabinoids to treat medical conditions is not supported by high-quality evidence. The scarcity of data precludes any solid conclusions regarding the efficacy and, especially, the safety of cannabinoids as therapeutic interventions. Further updating of the presented Cochrane systematic reviews also needs to carefully assess the quality of evidence, in order to better support healthcare decisions.

CONCLUSION
This review identified eight Cochrane systematic reviews (SRs) that provided evidence of unknown to moderate quality regarding the use of cannabinoids as a therapeutic intervention. These SRs found moderate-quality evidence regarding (a) benefits provided by cannabinoids (compared with placebo) for reducing nausea and vomiting that related to chemotherapy among adults and (b) lack of difference between cannabinoids and prochlorperazine regarding the number of participants in this subgroup who reported vomiting.