31
Cannabis Use in Medical Oncology: A Brief
Review
Uso de Canábis na Oncologia Médica: Uma Breve Revisão
José Sousa Vale1
1. Unidade Saúde Familiar Marginal, Administração Regional de Saúde de Lisboa e Vale do Tejo, ACES Cascais, Portugal Corresponding Author/Autor Correspondente:
José Sousa Vale, josepedrov9@gmail.com
Rua Egas Moniz 9010, 2765-618 São João do Estoril Received/Recebido: 19/04/2019; Accepted/Aceite: 28/08/2019 DOI: https://doi.org/10.25756/rpf.v11i2-3.218
Published/Publicado: 14/10/2019
© Autor(es) (ou seu(s) empregador(es)) 2019. Reutilização permitida de acordo com CC BY-NC. Nenhuma reutilização comercial. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use.
Abstract
Introduction: Nowadays, on cannabis and its use in clinical practice, one of the limiting factors may be
medical knowledge. This article seeks to dispel myths about medical cannabis and aims to explore the pharmacology, the possible current indications for cannabis use in the oncology area, more specifically the treatment of nausea and vomiting induced by chemotherapy, and in appetite loss, and to review the theo-retical aspects in the literature of its antineoplastic effect. Finally, also addresses some practical and clinical aspects of cannabis use.
Material and Methods: Three electronic databases (PubMed, Cochrane, and Google Scholar) were
searched between 1990 and 2018. The search strategy adopted the keywords “Cannabis”, “Medical Mari-juana”, “Medical Cannabis”, “Oncology”, “Chemotherapy-induced Nausea and Vomiting”.
Results: The search retrieved 300 records. After applying the inclusion and exclusion criteria, 42 articles
were selected for the synthesis of this paper. The results section in this narrative review was organized in subtopics (pharmacology, therapeutic forms, international use, nausea and vomiting, stimulation of appe-tite, antineoplastic effect and practical recommendations) to obtain a more linear narration.
Discussion: The exact place of cannabis in medical practice is still the subject of much debate, but the body
of evidence grows, and legislation is changing to reflect its increasing use. Public and medical opinions have also changed significantly regarding its utility in several medical conditions.
Conclusion: Further trials are necessary to assess the safety and efficacy of medical cannabis. Policies should
provide guidance regarding the application of current evidence on medical cannabis to clinical practice.
Keywords: Medical Marijuana; Nausea; Neoplasms/complications; Vomiting
Resumo
Introdução: No que respeita à canábis e o seu uso na prática clínica, um dos fatores limitantes atuais poderá
ser o conhecimento médico. Este artigo tem por fim esclarecer mitos sobre canábis medicinal, explorar a farmacologia, abordar possíveis indicações atuais para o uso da canábis na área oncológica, mais concre-tamente nas náuseas e vómitos induzidos por quimioterapia e no apetite, e ainda rever os aspetos teóricos presentes na literatura do seu efeito antineoplásico. Aborda-se também alguns aspetos práticos e clínicos da sua utilização.
32
Material e Métodos: Foram utilizadas três bases de dados (PubMed, Cochrane e Google Scholar) e a
estraté-gia de busca adotou as palavras-chave “Cannabis”, “Medical Marijuana”, “Medical Cannabis”, “Oncology”, “Chemotherapy-induced Nausea and Vomiting” e selecionando artigos publicados entre 1990 e 2018.
Resultados: A pesquisa resultou em 300 registos. Após aplicação dos critérios de inclusão e exclusão foram
selecionados 42 artigos para a síntese deste artigo. A secção de resultados desta revisão narrativa foi orga-nizada em subtópicos (farmacologia, formas terapêuticas, uso internacional, náusea e vómito, estimulação do apetite, efeito antineoplásico e recomendações práticas) para obter uma narrativa mais linear.
Discussão: O lugar exato da canábis na prática médica ainda é muito debatido, mas à medida que o corpo de
evidências cresce, a legislação muda para refletir o seu uso crescente. As opiniões pública e médica também têm mudado significativamente em relação à sua utilidade nas diversas situações clínicas.
Conclusão: Mais estudos são necessários para avaliar a segurança e a eficácia da canábis medicinal. As
polí-ticas devem fornecer orientações baseadas na evidência científica atual para a prática clínica.
Palavras-chave: Marijuana Medicinal; Náusea; Neoplasias/complicações; Vómitos
Introduction
Experience with the use of a certain drug, knowl-edge of its side effects, and its dose and method of administration are usually key aspects in the doctors' prescribing practice. Currently, regarding cannabis and its use in clinical practice, one of the limiting fac-tors may be medical knowledge. This article seeks to dispel myths about medicinal cannabis by exploring its pharmacology, current indications in the oncol-ogy area, more specifically the treatment of nausea and vomiting induced by chemotherapy and appetite loss, and to review the theoretical aspects in the lit-erature of its antineoplastic effect. Finally, this article also addresses some practical and clinical aspects of cannabis use.
Material and Methods
A search of literature was conducted to identify pa-pers regarding medical cannabis therapy related to patients’ oncology treatments. The author identified sources (abstracts and full text articles) from the PubMed, Cochrane and Google Scholar databases from 1990 to January 2018. Full texts published dur-ing 2019, referrdur-ing to abstracts presented prior to De-cember 2018 were also identified and analyzed. The search was narrowed to articles written in English and Portuguese. Medical Subject Headings (MeSH) terms were used in the search, including: “Cannabis”, “Medical Marijuana”, “Medical Cannabis”, “Oncol-ogy “, “Chemotherapy-induced Nausea and Vomit-ing”. In addition, the reference lists of the identified studies were manually reviewed to identify comple-mentary publications. Approximately 300 articles were screened. The following types of study were initially selected: systematic reviews, meta-analyses,
randomized controlled trials, clinical trials, cohort studies, longitudinal, prospective and retrospective studies, literature reviews, in vitro research, usual
practice, clinical experience, and case series studies. Meta-analyses and systematic reviews on the top-ics were preferred. During the screening step, stud-ies were excluded through an abstract assessment, followed by the full text if necessary. Articles were excluded for the following reasons: not a full-length article; duplicate study; no control groups and study of patients with other conditions other than cancer or chemotherapy induced nausea and vomiting. Er-rata and commentary were also excluded.
Results
The search returned 300 records. After applying the aforementioned methodology, 42 articles were se-lected to write this manuscript. The results section in this narrative review was organized in subtopics to obtain a more linear narration: pharmacology of the cannabinoid system, current existing therapeutic forms, examples of medical cannabis’ international use, cannabinoids effects on nausea and vomiting and appetite in the oncology setting, cannabinoids antineoplastic effect and some practical recommen-dations to medical cannabis use.
Pharmacology
Marijuana has its history in the field of medicine prior to the written word.1,2 The cannabis plant
con-tains more than 400 chemical constituents, of which more than 100 are cannabinoids.3 There are three
primary species of cannabis: Cannabis sativa, Canna-bis indica and CannaCanna-bis ruderalis.2 When the first
33 scientific interest due to its various properties,
among which: analgesic, inflammatory, anti-spasmodic, anticonvulsant, and has a role in appetite and sleep regulation.2,4,5 Cannabinoids are lipophilic
molecules that specifically bind to cells surface, that are better absorbed in the presence of fat, oils or polar solvents like ethanol.1,6
Cannabinoids are divided into three categories: phy-tocannabinoids, endocannabinoids and synthetic cannabinoids.6
Cannabis produces phytocannabinoids in acid form through unfertilized flowers, tetrahydroanabi-noid-a acid (THCA-A) and cannabidiol acid (CBDA), these being decarboxylated in a heat process into tet-rahydrocannabinol (THC) and cannabidiol (CBD), respectively, and for later consumption.1 THC
mim-ics the endogenous agonist of cannabinoid receptors, the endocannabinoids.7 THC also has euphoric,
anal-gesic, anti-emetic and anti-inflammatory properties.8
However, its medical potential is strongly limited by its psychoactivity.8 CBD has a lower affinity for
cannabinoid (CB) receptors and also interacts with other receptors, such as transient receptor potential vanilloid type 1 (TRPV1), G protein coupled recep-tor 55 (GPR55) or peroxisome proliferarecep-tor activated receivers (PPARs),7 and like THC, it has been shown
to have analgesic and anti-inflammatory properties, and, additionally, anticonvulsant, antipsychotic and neuro-protective properties.1,2,4-6
“Strains”, or chemovars, of the cannabis plant are in-dividual types of synthetic cannabis that are created to contain different concentrations of CBD and THC, and other components.9 The relative proportions of
these and other components are decisive for the pri-mary pharmacological effects and adverse events as-sociated with a particular cannabis chemovar.1,2,4,5
Reliably studying the effects of cannabis is complicat-ed by the large variety of available strains and by the numerous other compounds that cannabis contains, such as terpenes, flavonoids, phenols, amino-acids, and fatty acids among many others that have shown potential to modulate the plant’s pharmacological effect.1,2,4,5 It is known that the monoterpenes,10 as
myrcene, have analgesic and sedative properties, lim-onene has antidepressant and immunostimulatory properties, pinene inhibits acetylcholinesterase, and the beta-caryophyllene10 sesquiterpenoid presents
analgesic if anti-inflammatory effects.1,2,4,5
The endocannabinoid system consists of cannabi-noid receptors, their respective endogenous ligands and enzymes involved in the metabolism. The most
studied endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-Ag).11,12 The two
known cannabinoid receptors, CB1 and CB211,12
be-long to the family of G protein-coupled receptors.7
Most effects of cannabinoids on neurological and non-neurological tissues depend on activation of the CB1 receptor.11,12 Its high expression has been
ob-served in areas of the central nervous system that are involved in the modulation of motor behavior, mem-ory, learning, emotions, perception and endocrine functions.7,10 Activation of each receptor leads to the
inhibition of adenyl cyclase by means of G (Gi/o) proteins, which in turn activates metabolic pathways such as mitogen-activated protein kinase (MAPK), phosphatidylinusitol 3-kinase (PI3K) and cycloxige-nase-2 (COX-2) pathways, leading to the ceramide accumulation, and kinase-B protein (Akt) and ion channels modulation.2,6 Studies using CB1 knockout
mice suggest that this receptor plays a role in behav-ioral disorders, such as depression, anxiety, eating and cognition disorders.13 CB2 receptors were found
in cells of the immune system, but their presence was also revealed in the nervous system.14,15 In addition to
its neuromodulatory function, the endocannabinoid system has been shown to play a role in many other physiological pathways such as metabolism, immu-nity, cardiovascular and reproduction.2,6,9,16
Therapeutic Forms
Nabilone is one cannabinoid derived from THC and exists in oral form (containing 1 mg of nabilone per capsule). It is recommended to start with 1 mg per day and increase to a maximum of 2 to 3 mg per day.17
Dronabinol (Marinol®) is a synthetic form of THC that exists in capsules (2.5 mg, 5 mg, 10 mg), drops (25 mg/mL) and inhalation solution (10 mg/ mL).8 The initiation dose is 1-2mg (equivalent to
2-3 drops) per day, and it is recommended to increase up to a maximum dose of 30 mg per day.17
Cannabidiol has been approved by the Food and Drug Administration (FDA) as the first product based on CBD (Epidiolex®). Epidiolex® exists as an oily solu-tion (50 mg/mL, 100 mg/mL) and can be used in high daily doses of 10-20 mg/kg, but there is not much lit-erature on its use.17
Nabiximols (Sativex®) is a purified plant extract with CBD and THC. Nabiximols exists in oral spray and the medicine corresponds to 2.7 mg of THC and 2.5 mg of CBD.8 It is recommended to start with a
va-porization during the first two days, two vaporiza-tions on third and fourth day, and after up to a daily
34
maximum of twelve vaporizations.17 For trademark
purposes, purified CBD is marketed as Nabidiolex®, while THC is purified as the Tetrabinex® product. The cannabis flower, or more commonly known as medicinal cannabis, contains a mixture of different cannabinoids, terpenes and other organic substances. It is recommended to start with 25-100 mg of canna-bis flower, or 25-50 mg if THC content is more than 10%, and up to 100 mg if the THC content is low. It is recommended an increase of 25-100 mg every 1-3 days (corresponding to 2.5-5 mg THC).17
International Use
Nabiximols is legally approved in twenty-nine coun-tries (including Austria, Canada, Czech Republic, Denmark, France, Germany, Italy, Poland, Spain, Sweden, United Kingdom) for the treatment of spas-ticity in multiple sclerosis.1,6,17,18
In the United States of America (USA), nabilone is approved by FDA for the treatment of chemotherapy-induced nausea and vomiting (CINV), and sleep dis-orders; and dronabinol for human immunodeficiency virus (HIV) related weight loss.3,6 Epidiolex®, also
approved by the FDA, received orphan drug designa-tion for the treatment of two rare forms of epilepsy – Lennox Gastaut syndrome and Dravet syndrome – which are among the two types of epilepsy more difficult to treat.17,18
In Germany, dronabinol and nabilone are provided only by medical prescription and only with an opi-oid for patients in palliative care and suffering from chronic pain.18
Nabiximols is the only substance licensed in Israel with indication for the treatment of moderate to se-vere spasticity in multiple sclerosis, as well as an anal-gesic adjuvant in patients with advanced cancer, who are already treated with strong opioids.18
Dronabinol is approved in Canada for the treatment of HIV associated anorexia and weight loss, and severe CINV.18 Nabilone is only approved for severe CINV.18
In Canada, nabiximols is used as adjuvant treatment for the symptomatic relief of spasticity in patients with multiple sclerosis.18 It is also used “off-label” as
adjuvant treatment for symptomatic relief of neuro-pathic pain in adult patients suffering from multiple sclerosis and as adjuvant analgesic to the highest opioid tolerated dose for patients undergoing che-motherapy.18
In Portugal, the legalization of the use of can-nabis for medical purposes was promulgated by Law 33/2018 of July 18th.19 Decree-Law 8/2019, of
January 15th, regulated the principles and objectives
related to prescription, dispensation in pharmacy, pos-session and transportation, scientific research, regu-lation and supervision of activities related to the use of cannabis for medical purposes and information for health professionals.20 Portugal’s National Authority
for Medicines and Health Products (INFARMED, I.P.) determined the following therapeutic indications of nabiximols: spasticity associated with multiple sclero-sis or spinal cord injuries; nausea, vomiting (resulting from chemotherapy, radiation therapy and combined medication for hepatitis C and HIV); appetite stimu-lation in the palliative care of patients undergoing on-cological treatment or patients with acquired immu-nodeficiency syndrome; chronic pain (associated with oncological or nervous system diseases such as pain, neuropathic injury caused by nerve damage, phantom limb pain, trigeminal neuralgia, or following herpes zoster); Gilles de la Tourette syndrome; epilepsy and treatment of severe seizure disorders in childhood, such as Dravet and Lennox-Gastaut syndromes; and treatment-resistant glaucoma.21
Oncology
Nausea and Vomiting
It is estimated that 45% to 61% of patients with can-cer suffer from CINV,22 which occurs by activation
of neurotransmitters in the gastrointestinal tract by chemotherapeutic agents.23-25
Up to 32% of patients discontinue chemotherapy due to nausea and vomiting.26 In addition, CINV is
asso-ciated with an increase of total direct costs such as outpatient visits, emergencies, hospitalizations and medication, and indirect costs, such as impact on work productivity and absenteeism in the days fol-lowing the first cycle of chemotherapy.22
Cannabis is known for its anti-emetic properties, making it an attractive treatment for CINV. It has been proposed that THC can treat nausea through the emetic reflex pathways, acting on localized re-ceptors in the solitary tract nucleus of the area pos-trema.25 It has also been shown that THC reverses
the effects of 5-hydroxytryptamine 3 (5-HT 3) recep-tor agonists, which normally induce vomiting.25,27
It has been observed that THCA-A and CBDA can act as strong antiemetics in mice.1,2,4,5
Two systematic reviews have demonstrated benefits with the use of cannabinoids in patients undergoing chemotherapy.29,30 The treatment of some specific
areas of the body (abdomen, chest, brain) with ra-diation therapy can induce nausea, but there are few
35 reports of cannabinoids use in these situations.30,31
Two meta-analyzes reported significant improve-ments associated to cannabinoids treatment com-pared to conventional antiemetic therapy24,25 and
a meta-analysis5 confirms the antiemetic efficacy of
cannabinoids when compared to prochlorperazine. Nabilone, dronabinol and intramuscular levonantra-dol hydrochloride were tested as first-line anti-emet-ic agents to assess the complete absence of nausea and vomiting within the first 24 hours of chemo-therapy. It was concluded that cannabinoids were significantly more effective than prochlorperazine, metoclopramide hydrochloride, chlorpromazine, haloperidol, domperidone or alizapride in patients that followed medium emetogenic regimens (cyclo-phosphamide, methotrexate or fluorouracil), but not in those patients treated with highly emetogenic medicines (high doses of methotrexate, cisplatin or doxorubicin and cyclophosphamide).26,27
Ben Amar32 analyzed 15 randomized controlled
tri-als comparing nabilone to placebo or other available antiemetics as first-line agents. Nabilone was found to be superior to prochlorperazine, domperidone and alizapride, and dronabinol has a significantly greater antiemetic effect than chlorpromazine and equivalent to metoclopramide, tilperazine and haloperidol.32
Lane et al33 demonstrated that the combination of
dronabinol and prochlorperazine was significantly more effective than any single agent in the control of CINV. Meiri et al34 compared the administration
of dronabinol in combination with ondansetron and ondansetron alone for the treatment of CINV, con-cluding that dronabinol and ondansetron had similar efficacy for CINV, but the combined therapy was no more effective than either agent alone.
It should be noted that the studies included in these meta-analyzes differed in methodology, discontinuation rates, sample sizes, time of drug administration, type of tumor, and chemotherapeutic agents used, and, there-fore, are of limited use to draw significant conclusions. When analyzing the use of cannabis or cannabis ex-tracts to control nausea and vomiting, the published studies were either only observational or uncon-trolled, and data from randomized clinical trials for cannabis use is scarce.
Data on smoked cannabis is more limited, as there is no current data to compare with other types of can-nabis administrations.
Stimulation of Appetite
Data supporting the use of cannabinoids in appetite
stimulation is less conclusive than in CINV. When used in cancer patients with cachexia, cannabinoids appear to have a modest effectiveness. A study of the North Central Cancer Trial Group35 compared
the use of dronabinol with oral acetate megestrol and the two drugs combined. There was no statis-tical improvement in weight with dronabinol alone or in combination.35 A study using cannabis extract
in cancer patients from Germany, Netherlands and Switzerland also showed no benefit in terms of ap-petite or weight gain.36 Another study that tested
dronabinol demonstrated improvement in taste and subsequent consumption of protein, but this change did not translate into weight gain, although patients expressed improvement in their quality of life.30
Anecdotal reports from patients that routinely con-sume cannabis before chemotherapy confirm im-provement in quality of life and subsequent increased appetite and food intake.37
Better results were observed in studies of non-can-cer populations. Cannabis smoking in HIV patients resulted in a greater weight gain.38 A
placebo-con-trolled study in patients with dementia treated with dronabinol resulted in increased appetite and signifi-cant weight gain.39
Antineoplastic Effect
Activation of CB1 and CB2 receptors leads to a cascade of cellular activity affecting ion channels, production of cyclic adenosine monophosphate, and regulation of mitogen activated kinase proteins involved in cell sig-naling, proliferation, invasion, and adhesion.40
Cannabinoids can induce cancer cell death through cell signaling that lead to apoptosis.41
CB1 and CB2 receptor agonists have been shown to stimulate apoptotic cell death in glioma cells by in-ducing ceramide de novo synthesis, a sphingolipid with pro-apoptotic activity.5 The accumulation of
ceramide leads to an activation of the endoplasmic reticulum (ER) stress signaling pathway. This in-volves the expression of stress-regulated p8 protein (Nupr1), a transcriptional regulator involved in the control of tumor development, as well as its targets of the “downstream” chain, activating transcrip-tion factor 4 (ATF4), homologous protein C/EBP (CHOP) and tribbles homolog 3 (TRIB3), which in turn leads to an inhibition of mammalian target of rapamycin 1 complex (mTORC1) and eventually to autophagy-mediated cell death.5
It is disclosed that in hepatocellular carcinoma, cannabinoid induced ER stress can lead to protein
36
kinase activation by mitogen activated protein ki-nases (MAPK) and calcium/calmodulin dependent protein kinase 2 (CAMK), which in turn acts as an additional factor in autophagy-mediated cell death.5 In breast carcinoma and melanoma, it was demon-strated the cannabinoid inhibitory effect through Akt activation, which leads to the activation of pro-tein kinase inhibitors of p21 and p27 cyclins, causing phosphorylation of the retinoblastoma protein and, eventually, cell cycle arrest and apoptosis.5
It was shown that CBD reduces tumor cells viability in many types of cancers such as neuroblastoma, glio-blastoma, melanoma, leukemia, colorectal, breast, lung and prostate cancers.42
In addition, it has been reported inhibition of tumor angiogenesis via vascular endothelial growth factor (VEGF) blocking, and decreased invasion and dimin-ished lung tumor cell metastasis through over-regu-lation of intercellular adhesion molecule-1 (ICAM-1), which in turn has been associated with anti-meta-static cannabinoid action dependent on tissue in-hibitor of the metalloproteinase-1 matrix (TIMP-1).42 Practical Recommendations
The general approach in relation to dosing is to “start low, go slow and stay low”. All cannabis based me-dicinal products should be stored in a safe place in the same way as any other drug. Patients should take an inventory of symptoms, recording the response or efficacy of each cannabis product, and assisting phy-sicians determining the best treatment response. Smoking is the most common route of administra-tion, although not recommended because of the 600-900°C combustion that generates toxic
byprod-ucts, and the fact that the chronic use is associated with respiratory symptoms.1 In addition, mixing
can-nabis with tobacco increases the risk of respiratory malignancies.1
Vaporization heats cannabis up to 160-230°C, which produces significantly less harmful byproducts than smoking and is associated with fewer respira-tory symptoms. For inhalation of cannabis, patients should start with an inhalation and may increase one inhalation every fifteen to thirty minutes until the desired effect is achieved.1
Oils, capsules and other routes of administration are increasingly popular because of the convenience and accuracy of the dosage. The oral spray that contains nabiximols as active ingredient is currently the only cannabis-based prescription medicine. Oromucosal vaporization can be used for episodic symptom exac-erbations. Most patients require 6-8 sprays of
nabixi-mols per day for symptom relief with a limit of twelve sprays.1 For chronic symptoms and conditions, oral
preparations, such as nabilone, dronabinol and can-nabidol should be the basis of treatment due to lon-ger half-life.1
The topical route is ideal for local symptoms, such as muscle spasticity and pain, but there is not much lit-erature on this type of administration.1
The advantages and disadvantages of all administra-tion routes are summarized in Table 1.
Discussion
Physician myths act as barriers to medicines access, delaying disease treatment or symptomatic control. Many countries have new policies and legislation regarding marijuana, considering cannabis as a Table 1. Routes of administration summary
Start (min) 5-10 60-180 15 to 45 Variable Duration (h) 2-4 6-8 6-8 Variable Smoking/Vaporization [Cannabis Flower] Oral [Cannabidiol (Epidiolex®) Dronabinol (Marinol®) Nabilone (Cesamet®)] Oromucosal [Nabiximols (Sativex®) Purified CBD (Nabidiolex®) Purified THC (Tetrabinex®)] Topical
Benefits Preferable for acute symptoms
Preferable for chronic symptoms
Documented efficacy and safety
Preferred for localized symptoms
Disadvantages Expensive, non-portable vaporizers, require skill in use
Delayed start and titration challenge
Expensive, less available
37 possible treatment for various medical conditions,
and may therefore help reduce the medicine burden and improve symptomatic control in many patients. In Portugal the use of cannabis-based medicines, preparations and substances has recently been pro-mulgated, medicines or preparations based on the plant are approved by INFARMED, I.P., and can only be prescribed by a medical doctor.
However, questions are raised regarding the uncer-tainty of the efficacy of these therapies and the lim-ited evidence on which dosages are most correct.32-34
The currently available scientific evidence suggests that cannabis and its derived products have an anti-emetic effect in patients with CINV. In this context, cannabis and derived products are generally used as adjuvant treatments. However, experts consider the available evidence to be unhelpful.5,24,25,32-34 There
are also low-quality clinical studies that suggest that these products have a stimulant effect on appetite.37-39
It should be be given further attention to the evidence around the different antineoplastic effect theoretical models and more in vitro studies should be carried.
Conclusion
The prescription of cannabis for medicinal purposes makes sense and is scientifically defensible, without any myths, despite the different levels of evidence. Further studies are needed to evaluate the safety and efficacy of medicinal cannabis. Policies should provide guidance based on the current scientific evidence surrounding medical cannabis for clinical practice. Consideration should therefore be given to developing guidelines and health professionals should receive appropriate training on the use of cannabis for medicinal purposes, as the prescription of medicinal cannabis should occur only in precise clinical indications, in total respect for the leges artis.
Ethical Disclosures
Conflicts of interest: The authors have no conflicts
of interest to declare.
Funding Sources: This work has not received any
contribution grant or scholarship.
Provenance and Peer Review: Not commissioned;
externally peer reviewed.
Responsabilidades Éticas
Conflitos de Interesse: Os autores declaram não
possuir conflitos de interesse.
Fontes de Financiamento: O presente trabalho não
foi suportado por nenhum subsídio ou bolsa.
Proveniência e Revisão por Pares: Não
comissio-nado; revisão externa por pares.
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