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Cannabinoids for Medical Use a Systematic Review and Meta-analysis

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Therapeutic utilize of cannabis and cannabinoids: an show mapping and appraisal of systematic reviews

  • Ingrid Arevalo-Rodriguezii,
  • Solange Nuñez-Gonzálezone,
  • Andrés Viteri-García1 &
  • Daniel Simancas-Racines1

BMC Complementary Medicine and Therapies volume 20, Commodity number:12 (2020) Cite this article

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Groundwork

Although cannabis and cannabinoids are widely used with therapeutic purposes, their claimed efficacy is highly controversial. For this reason, medical cannabis use is a broad field of enquiry that is rapidly expanding. Our objectives are to identify, characterize, appraise, and organize the current available evidence surrounding therapeutic apply of cannabis and cannabinoids, using evidence maps.

Methods

Nosotros searched PubMed, EMBASE, The Cochrane Library and CINAHL, to identify systematic reviews (SRs) published from their inception up to December 2017. 2 authors assessed eligibility and extracted data independently. We assessed methodological quality of the included SRs using the AMSTAR tool. To illustrate the extent of apply of medical cannabis, we organized the results according to identified PICO questions using bubble plots corresponding to dissimilar clinical scenarios.

Results

A total of 44 SRs published between 2001 and 2017 were included in this prove mapping with data from 158 individual studies. We extracted 96 PICO questions in the following medical atmospheric condition: multiple sclerosis, movement disorders (e.grand. Tourette Syndrome, Parkinson Disease), psychiatry conditions, Alzheimer affliction, epilepsy, acute and chronic pain, cancer, neuropathic pain, symptoms related to cancer (east.k. emesis and anorexia related with chemotherapy), rheumatic disorders, HIV-related symptoms, glaucoma, and COPD. The evidence about these atmospheric condition is heterogeneous regarding the conclusions and the quality of the individual primary studies. The quality of the SRs was moderate to high according to AMSTAR scores.

Conclusions

Evidence on medical uses of cannabis is broad. All the same, due to methodological limitations, conclusions were weak in most of the assessed comparisons. Bear witness mapping methodology is useful to perform an overview of bachelor research, since it is possible to systematically depict the extent and distribution of evidence, and to organize scattered data.

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Background

Medical cannabis refers to the use of cannabis or cannabinoids for the treatment of a medical condition or to alleviate its associated symptoms [ane, 2]. The spectrum of substances categorized equally medical cannabis include: 1) Phytocannabinoids, which are found in cannabis herb and resins, e.g. Tetrahydrocannabinol (THC) and Cannabidiol (CBD); 2) Purified cannabinoids which originate from cannabis extracts (e.m. Nabiximols and purified cannabidiol); and 3) Synthetic cannabinoids (east.thou. Dronabinol and Nabilone) [2, iii].

Cannabis sativa produces more 100 phytocannabinoids and the biosynthesis of these substances depends on genomic background and specific environmental conditions [iv]. Additionality, in humans, the use of C. sativa has shown a myriad of heterogeneous key and peripheral effects due to endocannabinoid organization, whose receptors are scattered throughout the torso. The existence of many molecules, which perhaps modulate endocannabinoid system, complicates the scenario [five]. Currently, these are the reasons why, research on C. sativa is complex and hard.

The history of the utilize of cannabis for medical purposes is long, as these plants take been used for therapeutic purposes for more than 4000 years [6]. However, cannabis has a high-hazard contour and its medical utilise is highly controversial, even for therapeutic reasons. Despite the adverse effects of cannabis use such as hazard of developing cannabis dependence, exacerbation of cardiovascular disease, precipitation of psychotic disorders [7], and criticism to the evidence supporting its utilise for medical weather condition, several governments accept authorized the medical utilize of marijuana in countries such as Canada, the Czechia, Germany, Italy, kingdom of the netherlands, and 23 United states states [viii,9,x].

To approve the medical use of cannabis, well-designed and statistically powered clinical trials are necessary to investigate patient response [11]. Research on therapeutic uses of cannabis have restrictions due to limitations in gaining access to the quantity, quality, and type of cannabis product necessary to accost specific enquiry questions on health effects. There are notable inquiry challenges, such equally the vast spectrum of chemic substances considered as medical cannabis, the lack of dose standardization, and the lack of consensus about medical conditions for which cannabis accept been canonical. Evidence about the benefits and harms related to cannabis use is rapidly changing, making it difficult to identify and summarize findings in order to make informed decisions and constitute enquiry needs.

Prove mapping is a useful methodology to overview available research virtually wide knowledge areas. This methodology is useful to systematically describe the extent and distribution of evidence and to identify gaps for further research. This arroyo identifies if there is enough bear witness to back up policy maker'due south decisions and to recognize research-dense areas where systematic reviews can be conducted, as well equally research questions which should be prioritized in those fields.

The aim of this show mapping is to identify, characterize, appraise, and organize the currently available evidence about the therapeutic utilize of cannabis and cannabinoids through systematic reviews. Our arroyo aims to identify the clinical questions about efficacy of medical cannabis assessed in the scientific literature, equally well every bit to give an overview most their potential benefits and harms.

Methods

We followed the approach of the Global Show Mapping Initiative [12] with boosted components introduced by Ballesteros et al. [13,14,fifteen]. We established these criteria a priori in a protocol (available on asking). This testify map involved iii stages:

Systematic search strategy and selection of relevant studies

We used systematic reviews (SRs) as a comprehensive source of appraised testify. We defined medical cannabis every bit the use of cannabis or cannabinoids to treat a medical condition or to alleviate its symptoms. Thus, we based this show mapping in SRs assessing medical cannabis efficacy, effectiveness or prophylactic. We determine to include cannabis and cannabinoids as our objective is to identify all the available evidence related to medical cannabis, however cannabis and their isolated compounds could have different pharmacological backdrop and efficacy profiles. We considered SRs that conducted a search in at least two databases, and that appraise the quality or risk of bias of the included studies.

We excluded SRs focused on toll-effectiveness only. Additionally, nosotros excluded SRs assessing Rimonabant (i.e. a synthetic cannabinoid studied for weight command) since information technology acts as a functional antagonist of cannabinoids receptor [16].

Nosotros nerveless key search terms from previous reviews and SRs on medical cannabis by using natural and MeSH terms. Nosotros searched in PubMed, EMBASE, The Cochrane Library and CINAHL, from their inception up to December 2017. There were no linguistic communication restrictions.

We reviewed references in relevant articles to place potential additional reviews. Search strategies are reported in Additional file 1.

Later on duplicates were eliminated, two reviewers independently screened titles and abstracts (NMO, SNG) of the retrieved references and determined their relevance according to the eligibility criteria. On a second phase, full-texts of potentially relevant reviews were obtained for a terminal decision. Disagreements were resolved through discussion; if necessary, a third reviewer was consulted.

Information extraction of the included SRs

For included SRs, we collected information most their general characteristics, as well as information about the gathered data from individual studies. For data extraction, each reviewer went through a pilot test to standardize the procedure. We designed an extraction form to collect data at iii levels:

Characteristics of included SRs and methodological quality

We collected data nearly author(southward), year of publication, search engagement, searched databases, objective, pattern, number of included studies and patients, and methods used for the assessment of hazard of bias.

Two reviewers independently assessed the methodological quality of the included SRs by using the AMSTAR tool [17]. Disagreements were discussed until consensus was reached. We calculated a global AMSTAR score assigned one point for each item rated equally "yes" and items rated every bit "no"; "cannot answer", or "not applicable" obtained zip points, resulting in an overall score ranging from 0 to 11. Based on the reported score we classified each SR into three categories: low (0 to iii points), moderate (four to 7 points), and high quality (8 to eleven points) [17].

Clinical questions assessed in the SRs

We collected data related to research questions in PICO format (eastward.g. Population, Intervention, Comparator and Outcomes). For descriptive purposes, nosotros categorized conclusions reported by authors for each PICO question, into six categories: "unclear", "no consequence", "probably harmful", "harmful", "probably benign" and "beneficial", equally the categorization performed in previous evidence mapping. Come across Table i, for further details of the category definition. Ii reviewers independently categorized the conclusions. Discrepancies were discussed until consensus was reached. In all cases, judgement represented a formal cess nigh the prove, benefits and harms of each intervention.

Table one Classification of the conclusions according to results reported past authors

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Characteristics of individual studies included in SRs

We collected the post-obit information almost the individual studies included in each SR: abstract, number of included patients, country, funding, follow-up, type of study, condition, intervention, comparison, and methodological quality according to the authors of the SRs.

Synthesize the results into a user-friendly format

We presented our findings on tables and figures to draw the characteristics of the included SRs. Additionality, nosotros classified the data according to PICO questions. Thus, for each PICO we obtained the number of SRs, individual studies, and patients.

Nosotros mapped the extent of the evidence using bubble plots. Each chimera represents one SR. The chart displays information using three dimensions: (i) Authors conclusions ("unclear", "no result", "probably harmful", "harmful", "probably beneficial" and "beneficial") in the ten-centrality; (two) Score from AMSTAR assessment in the y-axis, and (three) The number of participants included in the SR assessing the PICO question represented in the chimera size. Systematic reviews may have been represented more than than once in the plot as 1 SR could have answered different PICO questions.

Results

Nosotros obtained a total of 1323 records after duplicates were removed. Following titles and abstracts screening, 93 manufactures were obtained in full-text for a final determination. Nosotros included a total of 44 SRs in the last pick (Fig. i). A list of excluded reviews with exclusion rationale is available in Additional file ii.

Fig. ane
figure 1

Flow chart outlining the study selection process

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Characteristics and quality of systematic reviews

Included SRs were published between 2001 and 2017 comprising studies conducted between 1975 and 2016. The last search was conducted in November 2016 [eighteen]. All but one SR assessed the effectiveness of cannabis or cannabinoids, while the remaining SR evaluated the cannabinoids adverse events merely [19]. Seventeen out of 44 included SRs performed a meta-analysis of data. See Table 2 for additional characteristics of SRs.

Tabular array 2 Characteristics of systematic reviews included in the Evidence Mapping

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Quality of the included SRs co-ordinate to AMSTAR scores was categorized as "low" in five studies (11,3%) [20,21,22,23,24], as "moderate" in 22 studies [nineteen, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,forty,41,42,43,44] and as "loftier" in 17 SRs [1, 45,46,47,48,49,50,51,52,53,54,55,56,57] (Fig. 2). The almost frequent drawbacks of SRs included no reporting of conflicts of interest, no assessment of publication bias, and absence of 'a priori pattern'.

Fig. 2
figure 2

Methodological quality of included Systematic Reviews

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Characteristics of individual studies

A full of 158 private studies were analyzed in these SRs, after considering duplication of studies. The number of included studies by review ranged from one [33, 39, 43, 46, 53, 58] to 79 [1]. Ane-hundred xl-six studies (92,4%) were randomized clinical trials (RCT), of which 59 were parallel and 84 were cross-over trials, and the remaining three studies did not have enough data to define the type of RCT. Two studies (1.2%) were not- randomized clinical trials (NRCT), vii (4,4%) were uncontrolled clinical trials, and three (1.9%) were observational studies.

Almost of the private studies were conducted in the Us (northward = 57; 36%), followed by the Britain (n = 29; xviii,3%), and Canada (due north = 10; vi,four%). Thirteen trials were conducted in more one country (8,3%). Forty-nine studies were funded past pharmaceuticals companies (31%) while 34 were funded past academic societies (21,9%). Follow-up of participants ranged from 1 day to 48 weeks. 1-hundred fifteen studies compared interventions of cannabis or cannabinoids with placebo. Characteristics of individual studies are provided in Additional file iii.

PICO questions

We extracted 96 PICO questions. PICOs were grouped in the following clinical scenarios. We provided details of PICOs in Additional file four.

Multiple sclerosis

The included SRs addressing the management of several symptoms associated to Multiple Sclerosis (MS), including pain, spasticity, float dysfunction, and tremor.

The largest number of SRs evaluated the consequence of medical cannabis on MS related pain. When cannabinoids in general were compared with placebo, the authors of two SRs (15 RCT) claimed a "probably beneficial" and "unclear" conclusion, respectively [29, 44]. For this indication, at that place were four different cannabis presentations: oromucosal cannabis spray, oral cannabis' extract, smoked cannabis and dronabinol, all which were compared with placebo. Two SRs claimed "probably beneficial" [23] and "unclear" [fifty] conclusions for oromucosal cannabis spray. Oral cannabis' excerpt was assessed in one SR and the authors ended a "beneficial" effect [23]. Two SRs yielded an "unclear" conclusion for smoked cannabis [23, 28]. Finally, in three SRs where the presentation was dronabinol the authors concluded a "probably beneficial" conclusion [23, 29, 30]. Merely one SR assessed the efficacy of Nabilone plus Gabapentin versus an active command (Gabapentin lone), the conclusion was "probably beneficial" [fifty].

When investigating spasticity, cannabinoids were compared with placebo in three SRs (12 RCTs). The authors of two SRs reported a "probably benign" conclusion [i, 31], and 1 an "unclear" conclusion [54]. Additionally, three assistants routes were compared with placebo. Oral cannabis extract containing THC / CBD was examined in three SRs (five RCTs). The results of two SRs were reported as "probably beneficial" [23, 50], and in ane the conclusion was "unclear" [24]. Oromucosal cannabis spray containing THC / CBD was studied in two SRs (v RCTs and i uncontrolled trial), that reported a "probably beneficial" conclusions [23, 24]. Smoked cannabis was assessed in three SRs (two RCTs), obtaining an "unclear" result [23], and "probably beneficial" conclusions [22, 50]. Finally, one SR compared THC-CBD (including both oral and oromucosal presentations) with THC lonely (three RCT), its results were reported every bit "unclear" [31].

In relation to bladder dysfunction, an SR (two RCTs and one NRCT) compared cannabis and placebo; authors concluded that cannabis is "probably beneficial" [eighteen]. Specific presentations of cannabis were compared with placebo. One SR evaluated oromucosal cannabis spray (ii RCTs), which was reported as "probably beneficial" [23]. In another SR, oral cannabis' excerpt was assessed in ii different formulations: forms containing THC and CBD with data from five RCT, and forms containing THC alone with information from two RCTs. The conclusion for both comparisons was "no effect" [23].

Finally, one SR focused on cannabis' upshot on tremor compared ii formulations containing THC and CBD with placebo. 1 formulation was oral cannabis excerpt (three RCT), and the other was oromucosal cannabis spray (two RCT). For both comparisons, the conclusion was "no effect" [23] (Fig. three).

Fig. 3
figure 3

Evidence mapping of cannabis uses in Multiple Sclerosis

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Movement disorders

Cannabinoids have been studied for symptomatic command of various involuntary movement atmospheric condition. In terms of Tourette Syndrome, 4 SRs compared oral cannabinoid (dose 2.5–xx mg) versus placebo (two RCTs), iii of them concluded that the effects were "unclear" and one as "probably beneficial" [ane, 23, 26, 44].

Regarding Parkinson'southward illness, one SR compared cannabis and cannabinoids versus placebo (ii RCTs) and reported an "unclear" conclusion [20]. For levodopa-induced dyskinesia, two SRs (one RCT) compared oral THC / CBD versus placebo and stated a "no effect" decision [23, 32].

For Huntington's illness cannabis was evaluated in one SR. This SR compared Nabilone and oral cannabidiol with placebo, each comparing included ane RCT. For both comparisons, the authors concluded an "unclear" upshot [23].

Finally, the effect of Dronabinol versus placebo for cramps in different conditions was evaluated. One SR (one RCT) evaluated the effect in amyotrophic lateral sclerosis and another SR (ane RCT) in Cervical Dystonia. Authors of both SRs reported an "unclear" effect [23, 46]. Encounter Fig. four.

Fig. 4
figure 4

Evidence mapping of cannabis uses in Movement Disorders, psychiatric weather and other neurological disorders

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Psychiatric atmospheric condition

Psychiatric conditions for which cannabis has been studied include: clinical depression, anxiety, sleeping disorders, and psychosis. Evaluating clinical depression, one SR (three RCTs) compared oromucosal cannabis spray containing THC and CBD versus placebo, the authors conclusion was "no effect" [1].

For anxiety disorders, 1 SR (one RCT), compared oral cannabidiol versus placebo, results were reported every bit "unclear" [1]. Likewise, for sleeping disorders, i SR (one RCT) contrasted Dronabinol with placebo, showing a "probably beneficial" conclusion [ane]. Finally, for psychosis one SR (two RCTs) evaluated oral cannabidiol versus no medical cannabis concluding as "no upshot" [one]. See Fig. 4.

Other neurological disorders

The medical utilize of cannabis has been assessed in a heterogeneous group of neurologic conditions. Two SRs compared oral Cannabidiol with placebo for patients with epilepsy (iii RCTs and one NRCT). Authors of both SRs obtained an "unclear" conclusion [23, 59].

Three SRs (two RCTs) evaluated Dronabinol compared with placebo to treat anorexia, disturbed beliefs and agitation in patients with Alzheimer'due south affliction. The conclusions of the authors were "probably benign" in ii SRs [32, 56] and "unclear" in one SR. [58]

In patients with an acute phase of acquired brain injury, Dronabinol was compared with placebo to manage intracranial pressure. The comparison was assessed in one SR (two RCTs), and it was concluded that in that location is "no issue" [37].

For the management of spasticity in patients with spinal string injury, two SRs (ane RCT) compared oral TCH with placebo. Authors concluded the effect to be "unclear" [36, 41]. See Fig. 4.

Pain in general

There is a large corporeality of prove surrounding cannabis and cannabinoids in the management of acute and chronic pain. Information technology has either been studied as an isolated symptom or in association with other diseases (i.eastward. diabetes mellitus or cancer).

Chronic hurting

Two SRs (37 RCTs) assessed cannabis and cannabinoids with placebo. One SR reported "probably harmful" furnishings [35], and one SR reported a "probably beneficial" effects [i]. One SR evaluated cannabinoids versus codeine (2 RCTs), results were reported to be "probably harmful" [25]. Vaporized cannabis was besides studied for chronic hurting relief compared to placebo in one SR. A "probably benign" determination was found in 21 patients involved in ane uncontrolled written report [22].

One SR focused on the comparison of cannabinoids' effects against placebo for chronic pain, non associated with cancer. This review included 9 RCTs for cannabis and cannabinoids, four RCTs for smoked cannabis, seven RCTs for oromucosal cannabis spray and two RCTs for dronabinol. The conclusions for these 4 comparisons were stated as "beneficial" [l]. Furthermore, oral cannabis extract was compared with placebo in 1 SR, with two patients. The authors stated a "no consequence" conclusion [25].

To consider the effects of cannabis and cannabinoids in neuropathic pain, 4 categories were established: neuropathic pain in general, posttraumatic neuropathic hurting, diabetic neuropathy, and neuropathic hurting associated with allodynia.

With regards to neuropathic pain in general, 3 SRs compared cannabis and cannabinoids versus placebo (21 RCTs), conclusions were reported every bit "beneficial", "probably benign", and "unclear" [21, 44, 51]. When cannabinoids were compared with placebo iii SRs were institute (15 RCTs) [29, 49, 57], two SRs concluded that cannabinoids were "probably beneficial" and 1 every bit "probably harmful". When just cannabis was included in comparison, the authors of one SR (four RCTs) stated a "probably beneficial" conclusion [28]. Furthermore, smoked cannabis, vaporized cannabis, oromucosal cannabis spray and CT-3 (an counterpart of THC-11-oic acid) were compared with placebo, with "probably benign" conclusions for all of these comparisons.

Furthermore, ii different cannabis presentations were compared with agile compounds in patients with neuropathic hurting. Ane SR assessed oral cannabis excerpt versus codeine (one crossover RCT with one patient), authors from this SR stated a "probably benign" conclusion [25]. 2 SRs (one RCT) that compare Nabilone with Dihydrocodeine stated conclusions considered as "no effect" [51, 57].

In relation to doses, two SRs (iii RCTs) compared low vs. high dosage of cannabis. Conclusions ranged from "probably beneficial" to "no effect" conclusions [22, 28].

For posttraumatic neuropathic pain, 3 comparisons were conducted. 1 SR evaluated smoked cannabis versus placebo (ane RCT), the conclusion was "unclear" [28]. Another SR compared Dronabinol with Diphenhydramine (i RCT), the conclusion was "no result" [36]. Regarding dose, one SR (one RCT) compared depression vs. high dosage of cannabis, it was concluded every bit "unclear" [22].

For diabetic neuropathy, ii cannabinoids presentations were compared with placebo. For Nabilone 1 SR concluded equally "probably benign" [fifty]. For cannabis spray (one RCT), the obtained results were considered "unclear" past one SR. [39] In addition, 1 SR (1 RCT) compared high with low doses of vaporized THC, results were considered as "probably beneficial" [22].

Finally, in patients with neuropathic pain associated with allodynia, one SR compared oromucosal cannabis spray with placebo, and concluded as "probably beneficial" [50].

Acute pain

Cannabinoids were compared with placebo in one SR (five RCTs). The conclusion from the authors was "unclear" [xl]. Likewise, Dronabinol and smoked cannabis were compared with placebo in ane SR, with the inclusion of two and ane RCT, respectively. The decision was rated by the authors as "probably benign" for Dronabinol and "unclear" for smoked cannabis [22]. The aforementioned SR, based on one RCT, evaluated smoked cannabis versus Dronabinol; it was concluded equally "unclear" [22].

The postoperative etiology of acute pain was assessed in two SRs, the intervention of Levonantradol was compared with placebo (two RCTs). One of these SRs showed a "probably beneficial" determination [25], while the other presented an "unclear" determination [40].

Two types of headaches were assessed in two SR. One SR, which included data of one observational written report, contrasted cannabis with no medical cannabis for patients with migraine, a "probably beneficial" conclusion was obtained [22]. The other SR compared Nabilone versus placebo in patients with headache due to medication overuse. The conclusion was "probably benign" [50]. Run across Fig. v.

Fig. 5
figure 5

Show mapping of cannabis use in pain

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Cancer

In patients with cancer, the almost frequent symptom studied was emesis induced by chemotherapy, comparisons were performed with placebo and with active controls.

Iv SRs compared cannabinoids with placebo (13 RCTs) [i, 42, 44, 55]. All these SRs stated a "probably beneficial" conclusion. One SR conducted a more specific comparing with Dronabinol versus placebo (3 RCTs), its conclusion was stated as "unclear" [34].

Cannabinoids were compared with conventional antiemetics in six SRs including a full of 31 RCTs [32, 34, 42, 44, 52, 55]. 2 SRs obtained a "probably beneficial" determination, two an "unclear" decision, and two concluded every bit "no effect". Meanwhile, one SR reported a "no effect" conclusion when compared cannabinoids plus antiemetic versus antiemetic alone (two RCTs and two NRCTs) [55].

Two SRs compared Dronabinol versus neuroleptics (four RCTs), one of these SRs concluded as "probably beneficial" and the other as "no effect" [32, 34]. Nabilone and Levonantradol were compared with neuroleptics past ane SR (7 RCTs for Nabilone and two RCTs for Levonantradol) that reported an "unclear" determination [34].

In relation to anorexia associated with cancer, cannabinoids were compared with placebo in one SR (three RCTs), the determination was stated as "no effect" [56]. As well, in one SR Dronabinol was compared with Megestrol with data from one RCT, the conclusion was "probably harmful" effect [56].

Regarding cancer pain, ane SR compared oral Benzopyranoperidine, oral THC and synthetic nitrogen analogue of THC with placebo. For Benzopyranoperidine, the conclusion from the authors was "no effect" (one RCT). For oral THC, the authors concluded as "probably benign" (two RCTs). For synthetic nitrogen analogue of THC (two RCTs), the conclusion was reported as "probably harmful" [25].

This SR also compared the furnishings of cannabinoids against codeine. In ii studies, one RCT for Benzopyranoperidine and ane RCT for oral THC, the authors ended "no effect" in both comparisons. In regards to the synthetic nitrogen analogue of THC based on the data from i RCT, the conclusion was reported every bit "probably harmful". Additionally, constructed nitrogen analogue of THC was compared with secobarbital in one RCT; the conclusion was stated as "probably harmful" [25]. For refractory cancer pain, one SR concluded as "probably benign" when compared oromucosal cannabis spray with placebo (two RCT) [56].

Finally, two SRs evaluated oromucosal cannabis spray versus placebo for the management of chemotherapy induced neuropathic pain. These SRs with data from 1 RCT concluded equally "unclear" and "no effect [50, 57]. Encounter Fig. 6.

Fig. half dozen
figure 6

Evidence mapping of cannabis uses in Cancer

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Other medical conditions

In this section, we described several conditions which were non included in the previous sections.

The utilise of medical cannabis has been studied in rheumatic disorders such every bit rheumatoid arthritis, fibromyalgia, Crohn'south disease, spinal chronic hurting, and osteoarthritis. For rheumatoid arthritis, oromucosal cannabis spray was compared confronting placebo in 3 SRs (1 RCT). Results were reported as "probably harmful", "unclear", and "probably beneficial" [47, 48, 53]. For fibromyalgia 2 comparisons were conducted in four SRs [27, 47, 48, 51] with data from one RCT. When comparing Nabilone versus placebo and Nabilone versus Amitriptyline - three SRs concluded as "probably beneficial" and one equally "unclear" for the offset comparison and the conclusions were "probably beneficial" in two and "no effect" in the other two SRs for the second comparison. In relation to Crohn's illness, ii SRs compared smoked cannabis with placebo (one RCT), both studies concluded this intervention as "probably beneficial" [33, 43]. For chronic spinal hurting, one SR compared Nabilone with placebo (one RCT), its determination was reported as "unclear" [48]. Finally, for osteoarthritis of the genu, the PF-04457845, a fat acid amide hydrolase-1 (FAAH1) inhibitor, was compared with placebo in two SRs (one RCT), in both SRs, authors stated that there was "no effect" [47, fifty].

In patients with HIV-AIDS, cannabis and cannabinoids were compared with placebo for general symptoms in three SRs (eight RCTs), conclusions were "unclear" in two, and "probably beneficial" in ane [1, 44, 60]. For HIV-related neuropathic hurting, smoked cannabis was compared with placebo in iii SRs (two RCTs), the conclusions were "unclear" in one and "probably benign" in two [22, 38, 51]. Regarding HIV wasting syndrome, three different comparisons were conducted. Herbal cannabis versus constructed cannabinoids was addressed in one SR (one RCT), the conclusion was "unclear" [56]. Ii SRs (five RCTs) compared Dronabinol with placebo and their conclusions were reported every bit "unclear" and "probably beneficial" [56, threescore]. Dronabinol was also compared with Megestrol in one SR (one RCT) and the conclusion was "no consequence" [56].

Glaucoma was another condition addressed in one SR (i RCT), where oromucosal cannabis spray was compared with placebo, the conclusion was reported as "unclear" [1].

Finally, in patients with chronic pulmonary obstructive disease, oromucosal cannabis spray was compared with placebo for the management of breathlessness in 1 SR (one RCT), the determination was "no result" [32]. See Fig. seven.

Fig. vii
figure 7

Evidence mapping of cannabis uses in other medical conditions

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Discussion

Our evidence mapping collected information from 44 SRs and 158 studies (most of them RCTs-92.4%) published between 2001 and 2017. The high number of studies reflects the increasing interest by users and physicians in assessing the potential therapeutic value of cannabis for several medical conditions.

We found that effectiveness and condom of medical cannabis has been evaluated in multiple medical conditions such as multiple sclerosis, movement disorders (e.chiliad. Tourette Syndrome, Parkinson Illness), psychiatric atmospheric condition, Alzheimer disease, epilepsy, astute and chronic pain, cancer, neuropathic pain, symptoms related to cancer (east.g. emesis and anorexia related with chemotherapy), rheumatic disorders, HIV-related symptoms, glaucoma, and COPD.

Medical conditions addressed by these SRs have been previously identified by surveys almost medical cannabis employ [59,60,61,64]. One of the nigh representative surveys showed that cannabis was primarily used for dorsum pain (11.9%), sleeping disorders (half dozen.9%), depression (6.7%), pain resulting from injury or accidents (vi.ii%), and multiple sclerosis (four.1%) [61].

Notwithstanding, nosotros noticed that the evidence for medical cannabis effects on these weather is heterogeneous regarding the conclusions and the quality of the collected studies. About of the conclusions extracted from SRs were classified as "probably beneficial" and "unclear". Furthermore, for some comparisons, conclusions claimed past SRs were inconsistent and even contradictory. One example was the comparing of cannabis and cannabinoids with conventional antiemetics for chemotherapy-induced emesis [32, 34, 42, 44, 52, 55], where two SRs found a "probably beneficial" conclusions, while remaining four SRs claimed for an "unclear" conclusion or "no effect¨.

The show supporting the medical employ of cannabinoids varies widely by clinical scenarios from high to low quality evidence. In fact, for some medical weather condition, that nosotros establish in this evidence map, studies cannot achieve firm conclusions, although RCTs have been conducted. While for other medical conditions, not showed in this evidence mapping, cannabis has been canonical for use with only preliminary data (pre-clinical studies or observational studies) supporting the employ, equally is the case of hepatitis C, chronic renal failure, and posttraumatic stress disorders [65].

The research on health furnishings of cannabis and cannabinoids has been limited by regulatory reasons and policies in some countries, leaving patients and health intendance professionals without the evidence to make decisions regarding the use of cannabis and cannabinoids in local scenarios. Some barriers have been identified to conducting basic, clinical, and population health enquiry on cannabis and cannabinoids, including regulations that restrict access to the cannabis products, funding limitations, and numerous methodological challenges [66].

In relation to funding, we constitute that about of the analyzed private studies were sponsored by pharmaceuticals companies. Because of complexity of the research agenda in this field more funding sources and machinery are needed to better sympathize the comprehensive wellness effects of cannabis.

In that location were likewise a number of methodologic limitations. The use of reliable placebos and well-selected active control compounds are needed for clinical trials, since the psychoactive and vasoactive effects of cannabis are a considerable claiming for effective blinding [66]. This limitation is important since 71% of the individual studies included in the SRs compared cannabis and cannabinoids against placebo.

Furthermore, restrictions on drug supply lead to the lack of standardization in potency or quantity of pharmacologically agile constituents in cannabis products [66, 67]. This bulwark leads to another limitation in conducting clinical trials reflecting in the wide variety of cannabis compounds assessed for a given medical condition.

Moreover, to get well-validated evidence it is necessary to take loftier-quality enquiry. The quality of the SRs was moderate to high according to AMSTAR scores. Still, the virtually frequent drawbacks were: failure to declare conflicts of interest, lack of likelihood of publication bias evaluation and absenteeism of 'a priori design'. Additionally, it'south important to land that across the quality of the SRs, its crucial to estimate the quality of the private primary studies to get a context of what evidence is telling the states.

1 strength of our bear witness mapping is the use of a sensitive and comprehensive search strategy to localize the 44 SRs included as a source of information. We also used a broad definition of SR in order to obtain the largest number of documents. Additionally, this testify mapping uses a friendly format to organize and allocate research questions in PICO format. Findings are shown graphically to allow the identification of enquiry needs, fields of controversy and the overall quality of the SRs included. Interventions were rated according to the conclusions stated by authors of the SRs. It is of import to consider that this classification does not represent the issue of the interventions.

One limitation of this evidence mapping is that the quality of the studies included in each SR was not evaluated in addition to the quality of the SRs. Furthermore, equally it is a characteristic of evidence mapping methodologies, we did non assess the quality of the show supporting the conclusions, which would accept required the use of some complementary methodology such equally GRADE. In addition, were describe the conclusions of the included studies according to how the authors declared them, all the same the direction of effects for each comparing should be securely assessed by systematic reviews. Despite these limitations, this evidence mapping meets its objective of organizing and describing the available evidence equally reported by the authors.

Conclusions

In conclusion, the bear witness on medical uses of cannabis is wide and highly heterogeneous. Yet, due to methodological limitations, conclusions were reported as "probably beneficial" and "unclear" in about of the assessed comparisons. To back up the use of cannabis in different clinical conditions boosted efforts are needed, as the approving for the use of cannabis and cannabinoids, as any other drug, should rely on well-designed and statistically powered clinical trials.

Testify mapping methodology is useful to perform an overview of available enquiry, since it is possible to systematically describe the extent and distribution of evidence, and to organize scattered data. This approach helps to identify if there is plenty evidence to support policy maker's decisions, to recognize research-dense areas where systematic reviews tin can be conducted, and to highlight research priorities in the field. To reach these objectives, SRs are a reliable source of information every bit they convey comprehensive and appraised data. Furthermore, SRs assist to expand or limit the scope of research mapping by modifying the search strategy co-ordinate to the evidence mapping aims.

Availability of information and materials

All data generated or analyzed during this written report are included in this published article [and its supplementary data files].

Abbreviations

AMSTAR:

Assessing the methodological quality of systematic reviews

CBD:

Cannabidiol

COPD:

Chronic obstructive pulmonary illness

FAAH1:

Fat acid amide hydrolase-1

HIV:

Human immunodeficiency virus

MS:

Multiple Sclerosis

NRCT:

Non-randomized controlled trial

PICO:

Population, intervention, comparing, consequence

RCT:

Randomized controlled trial

SRs:

Systematic reviews

THC:

Tetrahydrocannabinol

UCT:

Uncontrolled trial

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Acknowledgements

The authors would like to acknowledge Camila Montesinos-Guevara, Karol Quelal and Christopher Gault for their assistance with the edition of this paper.

Funding

This work was supported by Universidad UTE. This funding source had no role in the pattern, execution, analyses, estimation of the data, or conclusion to submit results.

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Affiliations

  1. Centro de investigación en Salud Pública y Epidemiología Clínica (CISPEC). Facultad de Ciencias de la Salud "Eugenio Espejo", Universidad UTE, Quito, Ecuador

    Nadia Montero-Oleas, Solange Nuñez-González, Andrés Viteri-García & Daniel Simancas-Racines

  2. Clinical Biostatistics Unit of measurement, Hospital Ramon y Cajal (IRYCIS), CIBER of Epidemiology and Public Health, Madrid, Spain

    Ingrid Arevalo-Rodriguez

Contributions

Conceived the study: NMO. Designed the study: NMO, SNG, DSR. Selection of studies: NMO, IAR, SNG. Extraction of information: NMO, IAR, SNG, AVG. Analyzed the data: NMO, SNG. Wrote the get-go draft of the manuscript: NMO, IAR, SNG, AVG, DSR. Contributed to the writing of the manuscript: NMO, SNG, AVG. Approved the concluding manuscript and conclusions: NMO, IAR, SNG, AVG, DSR. Authors read and canonical the concluding manuscript: NMO, IAR, SNG, AVG, DSR. The authors confirm the terminal commodity has been read and each writer's contribution has been approved by the appropriate writer.

Corresponding author

Correspondence to Nadia Montero-Oleas.

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Montero-Oleas, N., Arevalo-Rodriguez, I., Nuñez-González, Due south. et al. Therapeutic utilise of cannabis and cannabinoids: an evidence mapping and appraisement of systematic reviews. BMC Complement Med Ther 20, 12 (2020). https://doi.org/x.1186/s12906-019-2803-2

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Keywords

  • Cannabis
  • Cannabinoids
  • Medical marijuana
  • Evidence mapping
  • Evidence synthesis

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