Atividade antibacteriana dos canabinoides sobre a bactéria causadora da tuberculose: uma revisão sistemática

 

 

Gisele Aparecida Soares Cunha de Souza¹, Rubia Laine de Paula Andrade², Giordano Novak Rossi³, Rafael Guimarães dos Santos⁴, Jaime E. C. Hallak⁴, Nathalia Halax Orfão⁵

 

¹  Curso de Medicina, Núcleo de Saúde, Fundação Universidade Federal de Rondônia. Porto Velho, RO, Brazil.

²  Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo. Ribeirão Preto, SP, Brazil.

³  Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.

⁴  Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil. Instituto Nacional de Ciência e Tecnologia – Medicina Translacional, Ribeirão Preto, São Paulo, Brazil.

⁵  Departamento de Medicina, Fundação Universidade Federal de Rondônia. Porto Velho, RO, Brazil.

 

Received on 11/22/2023

Approved on 11/23/2023

DOI: 10.21877/2448-3877.202300154

 

INTRODUCTION

 

Studies of the pharmaceutical potential of Cannabis’ active ingredients have increased after the discovery of the endocannabinoid system and the endogenous CB1 and CB2 receptors which, when activated, interfere with various signaling pathways, causing different effects on tissues and organs.⁽¹⁾

Cannabinoids are involved in pathophysiological processes (pain and inflammation) and can act on the gastrointestinal (modifying mobility and secretion, used as antiemetics⁽²⁾), cardiac (reducing atrial contraction and causing hypotension through the activation of cannabinoid receptors⁽³⁾), and pulmonary systems (with anti-inflammatory effect mediated by endocannabinoid metabolic pathways⁽⁴⁾), among others.

Studies show that CB1 and CB2 receptors are present in the lungs and bronchi, responding to endocannabinoids, synthetic cannabinoids, and phytocannabinoids.⁽⁵⁾ Tetrahydrocannabinol (THC), for example, can activate these receptors, while cannabidiol (CBD) and cannabinol (CBN) modulate cellular functions⁽⁴⁾. Exposure of lung tissue to the endocannabinoid anandamide, for example, causes hypoxic pulmonary vasoconstriction⁽⁶⁾, while synthetic cannabinoids induce lung inflammation.⁽⁷⁾

Infection of the lungs by the bacterium Mycobacterium tuberculosis is effectively controlled in most individuals due to the immune response of macrophages, dendritic cells, and fibroblasts, forming a granuloma and preventing the progression of the infection to tuberculous disease, called latent infection.⁽⁸⁾ A study showed that granuloma formation and disease containment is dependent on the early migration of alveolar macrophages to the interstitium induced by interleukin 1 (IL-1R), which defines whether the immune response will be Th1 or Th17 (faster or slower, respectively), determining the severity of the disease.⁽⁹⁾ COX-2 metabolites of endocannabinoids regulate the functions of alveolar macrophages that have CB1 and CB2 receptors on their membranes.^(4,10,11)

The impacts of (endo)cannabinoids when activating these receptors in the lung are still unclear. However, one study shows that the activation of cannabinoid receptors on alveolar macrophages selectively inhibits the release of angiogenic and lymphogenic factors, which may assist in vascular remodeling during chronic inflammation.⁽¹⁰⁾ Another study, in turn, showed that the CBD improves lung function and decreases inflammation in a mouse model.⁽¹²⁾

Given the above, this study aimed to identify the existence of the antibacterial activity of cannabinoids against M. tuberculosis.

 

MATERIAL AND METHODS

 

This is a systematic review of scientific literature registered in the International Prospective Register of Ongoing Systematic Reviews (PROSPERO) under the ID CRD42021253894, following the guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta Analyzes (PRISMA).⁽¹³⁾

The guiding question “Do cannabinoids have antibacterial activity against Mycobacterium tuberculosis?” was defined using the acronym PEO,⁽¹⁴⁾ in which P (Population) corresponded to M. tuberculosis, E (Exposure), to cannabinoids, and O (Outcome) was related to antibacterial activity.

The inclusion criteria were experimental, pre-clinical and clinical studies that evaluated the effects of phytocannabinoids or synthetic cannabinoids on M tuberculosis. Articles that addressed the effects of endocannabinoids were excluded, as well as those that assessed the risk of acquiring tuberculosis with the recreational use of cannabinoids. It should be noted that in order to reach a greater number of publications on the topic, no time frame, country/continent or language of publication was established for the bibliographic survey.

For the search expression, free and controlled vocabulary was used, composed of terms indexed in the Health Sciences Descriptors (DeCS), Medical Subject Headings (MeSH) and Embase Subject Headings (Emtree), with their respective synonyms in Portuguese, English and Spanish, combined using the Boolean operators OR and AND (Table 1).

 

Table 1

Simplified search strategy in English used in databases.

Acronym	Keyword	Search vocabulary
Population	Mycobacterium tuberculosis	“Mycobacterium Tuberculosis”
Exhibition	Canabinoids	(Cannabis OR Bhang OR Bhangs OR Cannabi OR “Cannabis indica” OR “Cannabis indicas” OR “Cannabis sativa” OR “Cannabis sativas” OR Ganja OR Ganjas OR Hashish OR Hashishs OR Hemp OR “Hemp Plant” OR “Hemp Plants” OR Hemps OR “indicas, Cannabis” OR Marihuana OR Marihuanas OR Marijuana OR Marijuanas OR “Plant, Hemp” OR “Plants, Hemp” OR “sativas, Cannabis” OR Cannabinoids OR phytocannabinoids OR Canabidiol OR cannabidiol OR Dranabinol OR THC OR Tetra-Hidrocanabinol OR Tetraidrocanabinol OR Canabigerol OR canabicromeno OR  canabiciclol OR canabielsoin OR canabinol OR canabinodiol OR canabitriol OR “Medical Marijuana” OR “Marijuana, Medical” OR “Medical Cannabis” OR “Cannabis, Medical” OR “Marijuana Treatment” OR “Treatment, Marijuana” OR “Medical Cannabis” OR “Cannabis, Medical” OR “Marijuana Dispensaries” OR “Dispensaries Marijuana”)
Outcome	Antibacterial activity	(“Antibacterial Agents” OR “Antimycobacterial Agents” OR “Anti-Bacterial Compounds” OR “Bacteriocidal Agents” OR Bacteriocide OR “Bacteriostatic” OR “antitubercular Agents” OR “Anti-Tuberculosis Agent” OR “Tuberculostatic Agent” OR “Antitubercular Antibiotics”)

Made by the authors

 

 

The search was carried out on August 22, 2022 in the databases LILACS, PubMed, EMBASE, Scopus, Web of Science, PsycINFO, BMC’s BioMed Central Journals, Cochrane Library, Epistemonikos, Health Systems Evidence and Center for Review Dissemination. At LILACS, the search was carried out in English, Portuguese and Spanish. In the other databases, English was used. Furthermore, gray literature was limited to study protocol registration databases recommended in the Methodological Guidelines of the Ministry of Health,⁽¹⁵⁾ such as Clinical Trials and the gray literature databases Open Grey, Gray Literature Report, Scientific Repository of Open Access of Portugal (RCAAP), Brazilian Digital Bank of Theses and Dissertations (BDTD), and Google Scholar. A manual search was also carried out by checking the references cited in the included articles.

Subsequently, the publications were exported to the Qatar Computing Research Institute’s Rayyan QCRI online reference manager⁽¹⁶⁾ for study selection. This selection was made through reading and analysis of titles and abstracts by two independent reviewers, whose disagreements were resolved by a third reviewer.

The selected articles proceeded to the full reading stage and confirmation of eligibility occurred with the articles that presented a description of the antibacterial effects of cannabinoids in tuberculosis. Subsequently, for data extraction and analysis, a synthesis matrix was created with author, year, objective and study design, in addition to the main results, article quality, methodological quality and relevance. The risk of bias assessment was also included, which was carried out using the ROBIS⁽¹⁷⁾ an instrument which evaluates three domains: pre-intervention (confounding, selection of study participants), at the time of the intervention (bias in the classification of the intervention), and post-intervention (deviation from the intended intervention, missing data, measurement of the outcome, selective reporting of results).

 

RESULTS

 

486 publications were found, of which 379 were identified in databases, 104 in gray literature and 3 through manual search. Among these, 15 publications were excluded due to duplication and 471 were considered for reading the title and abstract, with 11 studies being selected for reading in full. Of these 11, 5 were excluded because they were secondary studies, 3 because they did not address the use of cannabinoids (Hops, Polygonatum officinale and rimonabant), and 1 for not answering the guiding question. Therefore, 2 articles were considered eligible for our review. Figure 1 demonstrates the selection and inclusion and exclusion process of articles.

In the present review, a pre-clinical in vitro study⁽¹⁸⁾ and a pre-clinical study carried out with animals were included.⁽¹⁹⁾ The antibacterial activity of CBD was identified in both studies, although this was less evident in the study due to Blaskovich et al. (2021).⁽¹⁹⁾ The results in more detail are presented in Table 2.

When the quality of the articles was verified, Abichabki et al. (2021)⁽¹⁸⁾ were evaluated with a final grade of 58.7%, as they did not mention the purity and solubility of the test, the cell passage number, the measures taken to avoid contamination by mycoplasma, bacteria, fungi and viruses, the cell density, statistical methods, software used, funding sources and conflict of interests. The article by Blaskovich et al. (2021)⁽¹⁹⁾ received a final grade of 91.9%, as they did not mention the test’s solubility and metabolic competence.

 

Figure 1

Flowchart of articles included in this systematic review, 2022

Modified from Page et al. (2020)⁽¹³⁾

Table 2

Summary of the results of the articles included in this systematic review.

Author and year	Objective	Design	Main results	Article quality	Method quality	Relevance
Abichabki et al., 2021(18)	To evaluate the antibacterial activity of ultrapure cannabidiol (CBD) against a wide diversity of Gram-negative (GN) and Gram-positive (GP) bacteria (44 different species, 95 strains), comprising standard strains and clinical isolates, and to investigate the antibacterial activity of the CBD + PB combination against GN bacteria, including chromosomal and plasmid-acquired PB-resistant and intrinsically PB-resistant GNB.	In vitro	CBD exhibited antibacterial activity against different species of bacteria, including Mycobacterium tuberculosis, which causes TB, at a minimum inhibitory concentration of CBB for Mycobacterium tuberculosis H37Rv (MIC = 9.37 ± 1.88 µg / mL) 117 and MDR M. tuberculosis CF86 (MIC = 18.78 ± 5.95 µg / mL), which should be included in clinical trials with promising efficacy.	58,7	100	Directly relevant
Blaskovich et al., 2021(19)	Verify the antimicrobial activity of CBD in different Gram-positive/negative bacteria	In vivo	CBD showed discrete activity against M. tuberculosis H37Rv (MIC>64 µg mL -1, although with 70% inhibition at 64 µg mL)	91,9	100	Directly relevant

 

DISCUSSION

 

Despite the extensive search carried out in the literature, only two studies were identified that addressed the effect of cannabinoids as an antimicrobial agent for Mycobacterium tuberculosis, the causative agent of tuberculosis. In view of this finding, it is worth highlighting the need for more clinical and pre-clinical studies that investigate this effect, especially considering that one of the aforementioned articles⁽¹⁸⁾ presented a low percentage of approval in relation to its quality.

Regarding the results of the two studies, there was a difference in the minimum inhibitory concentration (MIC) of CBD to observe the antimicrobial effect for the Mycobacterium tuberculosis H37Rv strain, with the study Abichabki et al. (2021)⁽¹⁸⁾ smaller than Blaskovich et al. (2021)⁽¹⁹⁾ (9.37 µg/mL and <64 µg/mL, respectively). This difference may be related to the study method, since the first was in vitro and the second involved infection of pig tissue and subsequent treatment with CBD.

Furthermore, there was a difference between the incubation time and addition of other components: in the study by Blaskovich et al. (2021),⁽¹⁹⁾ 0.02% resazurin and Tween-80 were added to each well with incubation for 5 days; in the study by Abichabki et al. (2021),⁽¹⁸⁾ there was no addition of resazurin, and the incubation was 7 days. The effect of CBD in relation to the multidrug-resistant Mycobacterium tuberculosis strain CF86 was also analyzed in the study by Abichabki et al. (2021)⁽¹⁸⁾ and presented an MIC of 18.78 µg/mL.

The main limitation of this review is the low number of articles found. There are only two of them, the results of our search demonstrate that very little is still known about the possible therapeutic effects of CBD for the treatment of tuberculosis and highlights the need for further investigations in the area.

 

CONCLUSION

 

From the preliminary results reported, there appears to be a possible therapeutic effect of CBD for the treatment of tuberculosis. Despite this, it is not known whether other cannabinoids have this potential or which one is supposed to be more effective. Therefore, this review is limited by the available evidence and makes clear the need for other studies involving the use of cannabinoids and their effects on M. tuberculosis.

 

REFERENCES

 

1. Lowe H, Toyang N, Steele B, Bryant J, Ngwa W. The endocannabinoid system: a potential target for the treatment of various diseases. Int J Mol Sci. 2021; 22(17):9472. doi: 10.3390/ijms22179472.
2. Hasenoehrl C, Taschler U, Storr M, Schicho R. The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease. Neurogastroenterol Motil. 2016; 28(12):1765-80. doi: 10.1111/nmo.12931.
3. Bonz A, Laser M, Kullmer S, Kniech S, Babin-Ebell J, Poop V, et al. Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol. 2003; 41(4):657-64. doi: 10.1097/00005344-200304000-00020.
4. Turcotte C, Blanchet MR, Laviolette M, Flamand N. Impact of cannabis, cannabinoids, and endocannabinoids in the lung. Front Pharmacol. 2016; 7:317. doi: 10.3389/fphar.2016.00317
5. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995; 232(1):54-61. doi: 10.1111/j.1432-1033.1995.tb20780.x.
6. Welzen D, Matthey M, Bindila L, Lerner R, Lutz B, Zimmer A, et al. Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci USA.2013; 110(46):18710-5. doi: 10.1073/pnas.1308130110.
7. Zawatsky CN, Abdalla J, Cinar R. Synthetic cannabinoids induce acute lung inflammation via cannabinoid receptor 1 activation. ERJ Open Res. 2020; 6(3):00121-2020. doi: 10.1183/23120541.00121-2020.
8. Moutinho ILD. Tuberculosis: immunological aspects in the infection and in the disease. Revista Med Minas Gerais. 2011; 21(1):42-8. Disponível em: http://rmmg.org/artigo/detalhes/289.
9. Lovey A, Verma S, Kaipilyawar V, Ribeiro-Rodrigues R, Husain S, Palaci M, et al. Early alveolar macrophage response and IL-1R-dependent T cell priming determine transmissibility of Mycobacterium tuberculosis strains. Nat Commun. 2022; 13(1):884. doi: 10.1038/s41467-022-28506-2.
10. Staiano RI, Loffredo S, Borriello F, Iannotti FA, Piscitelli F, Orlando P, et al. Human lung-resident macrophages express CB₁ and CB₂ receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors. J Leukoc Biol. 2016; 99(4):531-40. doi: 10.1189/jlb.3HI1214-584R
11. Matias I, Pochard P, Orlando P, Salzet M, Pestel J, Di Marzo V. Presence and regulation of the endocannabinoid system in human dendritic cells. Eur J Biochem. 2002; 269(15):3771-8. Doi: 10.1046/j.1432-1033.2002.03078.x.
12. Ribeiro A, Almeida VI, Costola-de-Souza C, Ferraz-de-Paula V, Pinheiro ML, Vitoretti LB, et al. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol Immunotoxicol. 2015; 37(1):35-41. doi: 10.3109/08923973.2014.976794.
13. Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021; 372:n160. doi:10.1136/bmj.n160.
14. Moola S, Munn Z, Sears K, Stefcu R, Currie M, et al. Conducting systematic reviews of association (etiology): the Joanna Briggs Institute’s approach. Int J Evid Based Healthc. 2015; 13(3):163-9. Doi: 10.1097/XEB.0000000000000064.
15. Ministério da Saúde. Secretaria de Ciências, tecnologia, inovação e insumos estratégicos em Saúde. Departamento de Gestão e Incorporação de Tecnologias em Saúde. Diretrizes metodológicas: elaboração de revisão sistemática e mata-análise de ensaios clínicos randomizados. Brasília: Ministério da Saúde, 2021. Acesso: https://rebrats.saude.gov.br/images/Documentos/2021/20210622_Diretriz_Revisao_Sistematica_2021.pdf
16. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan – a web and mobile app for systematic reviews. Syst Rev. 2016; 5(1):210. doi https://doi.org/10.1186/s13643-016-0384-4.
17. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomized studies of interventions. BMJ 2016; 355:i4919. doi: 10.1136/bmj.i4919.
18. Abichabki N, Zacharias LV, Moreira NC, Bellissimo-Rodrigues F, Moreira FL, Benzi JRL, et al. Cannabidiol (CBD) repurposing as antibacterial: promising therapy of CBD plus polymyxin B against superbugs. Sci Rep. 2022; 12(1):6454. doi: 10.1038/s41598-022-10393-8.
19. Blaskovich MAT, Kavanagh AM, Elliott AG, Zang B, Ramu S, Amado M, et al. The antimicrobial potential of cannabidiol. Commun Biol. 2021; 4(1):7. doi: 10.1038/s42003-020-01530-y.

Correspondence

Gisele Aparecida Soares Cunha de Souza

E-mail: [email protected]