Growing demand for cannabis-based products

Brazil spent around BRL 165 million with the public supply of cannabis-derived products from 2015 to mid-2023, with about half of this amount resulting from lawsuits filed against the government ¹1. Kaya Mind. Anuário da cannabis medicinal no Brasil 2023. https://kayamind.com/anuario-da-cannabis-medicinal-no-brasil-2023/ (accessed on 20/Apr/2023).
https://kayamind.com/anuario-da-cannabis... . A Federal Bill ²2. Senado Federal. Projeto de Lei nº 89 de 2023. Institui a Poli´tica Nacional de Fornecimento Gratuito de Medicamentos Formulados de Derivado Vegetal a` Base de Canabidiol, em associac¸a~o com outras substa^ncias canabinoides, incluindo o tetrahidrocanabinol, nas unidades de sau´de pu´blicas e privadas conveniadas ao Sistema U´nico de Sau´de - SUS. https://legis.senado.leg.br/sdleg-getter/documento?dm=9251801&ts=1681737802431&disposition=inline#:~:text=Institui%20a%20Política%20Nacional%20de,Sistema%20Único%20de%20Saúde%20-%20SUS (accessed on 03/May/2024).
https://legis.senado.leg.br/sdleg-getter... is currently being analyzed in Brazil’s Chamber of Deputies to establish the National Policy for the Supply of Cannabis-Derived Products by the Brazilian Unified National Health System (SUS, acronym in Portuguese). Several bill have already been passed or are under analysis in several states and municipalities nationwide ³3. Escola Politécnica de Saúde Joaquim Venâncio, Fundação Oswaldo Cruz. Novos tempos: cannabis medicinal ganha espaço no SUS. https://www.epsjv.fiocruz.br/noticias/reportagem/novos-tempos-cannabis-medicinal-ganha-espaco-no-sus (accessed on 20/Apr/2023).
https://www.epsjv.fiocruz.br/noticias/re... .

The growing interest in these products is also the result of the work of several entities, which focus on the growth and artisanal manufacture of cannabis-derived products for medicinal purposes ⁴4. Rodrigues APLS, Lopes IS, Mourão VLA. Sobre ativismos e conhecimentos: a experiência de associações canábicas no Brasil. Ciênc Saúde Colet 2024; 29:e18462022.. The scenario also shows the emergence of industries in Brazil, which have sanitary authorization to manufacture and sell, as well as importers that facilitate the entry of numerous products authorized for import, coming from several countries such as the United States, the United Kingdom, Switzerland, the Netherlands, and Uruguay ⁵5. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 327, de 9 de dezembro de 2019. Dispõe sobre os procedimentos para a concessão da Autorização Sanitária para a fabricação e a importação, bem como estabelece requisitos para a comercialização, prescrição, a dispensação, o monitoramento e a fiscalização de produtos de Cannabis para fins medicinais, e dá outras providências. Diário Oficial da União 2019; 11 dec.^,66. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 660, de 30 de março de 2022. Define os critérios e os procedimentos para a importação de produto derivado de Cannabis, por pessoa física, para uso próprio, mediante prescrição de profissional legalmente habilitado, para tratamento de saúde. Diário Oficial da União 2022; 31 mar..

The established demand is encouraged by advertising campaigns announcing the therapeutic benefits of cannabis-derived products and promoting their alleged and diverse medicinal properties, most of which still lack scientific evidence to support their use by the population. This supply contributes to the understanding that any product containing cannabis should be considered a medicine; however, what has been seen is the idea of products and cannabis itself as a panacea ⁷7. Portela R, Mota DM, Ferreira PJG, Lula MD, Reis BB, Oliveira HN, et al. Judicialização de produtos à base de canabidiol no Brasil: uma análise de 2019 a 2022. Cad Saúde Pública 2023; 39:e00024723..

Regulatory framework and evidence for cannabis use

In Brazil, there is only one cannabis derived product classified as a medicine. The medical use of these products is a controversial issue, as Cannabis sativa is considered a prohibited plant according to Brazilian Minstry of Health Ordinance n. 344/1998 (list E) ⁸8. Ministério da Saúde. Portaria nº 344, de 12 de maio de 1998. Aprova o Regulamento Técnico sobre substâncias e medicamentos sujeitos a controle especial. Diário Oficial da União 1998; 31 dec.. However, since cannabidiol (CBD) started being used to treat refractory epilepsy in children, there has been an increase in demand for its medical use in Brazil ⁹9. Conselho Federal de Medicina. Resolução CFM nº 2.113, de 16 de dezembro de 2014. Aprova o uso compassivo do canabidiol para o tratamento de epilepsias da criança e do adolescente refratárias aos tratamentos convencionais. Diário Oficial da União 2014; 16 dec.. Brazilian Health Regulatory Agency (Anvisa, acronym in Portuguese) included CBD in the C1 list, the same classification as other substances under special control ¹⁰10. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 3, de 26 de janeiro de 2015. Dispõe sobre a atualização do Anexo I, Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial, da Portaria SVS/MS nº 344, de 12 de maio de 1998 e dá outras providências. Diário Oficial da União 2015; 28 jan..

In this context, regulations for the medical use of cannabis have been developed in the country. Resolutions have authorized the import of cannabis-containing products, provided that their producers or distributors are authorized by the health authorities of their countries of origin ¹¹11. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 17, de 6 de maio de 2015. Define os critérios e os procedimentos para a importação, em caráter de excepcionalidade, de produto à base de canabidiol em associação com outros canabinoides, por pessoa física, para uso próprio, mediante prescrição de profissional legalmente habilitado, para tratamento de saúde. Diário Oficial da União 2015; 8 may.^,1212. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 66 de 18 de março de 2016. "Dispõe sobre a atualização do Anexo I (Listas de substâncias entorpecentes, psicotrópicas, precursoras e outras sob controle especial) da Portaria SVS/MS nº 344", de 12 de maio de 1998 e dá outras providências. Diário Oficial da União 2016; 18 mar.. Currently, Resolution n. 660 establishes the criteria and procedures for import by individuals for personal use only, and with a prescription from a healthcare professional ⁶6. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 660, de 30 de março de 2022. Define os critérios e os procedimentos para a importação de produto derivado de Cannabis, por pessoa física, para uso próprio, mediante prescrição de profissional legalmente habilitado, para tratamento de saúde. Diário Oficial da União 2022; 31 mar..

Anvisa has established requirements for marketing, prescribing, dispensing, monitoring, and inspection of products authorized for manufacture in Brazil, which can only be sold in ready-made form (compounding not authorized) and with a medical prescription. Products with up to 0.2% THC require a “B”-type prescription, and those with a higher content for palliative care should have an “A”-type prescription ⁵5. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 327, de 9 de dezembro de 2019. Dispõe sobre os procedimentos para a concessão da Autorização Sanitária para a fabricação e a importação, bem como estabelece requisitos para a comercialização, prescrição, a dispensação, o monitoramento e a fiscalização de produtos de Cannabis para fins medicinais, e dá outras providências. Diário Oficial da União 2019; 11 dec..

On the other hand, the legal establishment authorized patient associations to grow, compound, prepare, produce, store, transport, dispense, and research C. sativa¹³13. Tribunal Regional Federal da 5ª Região. TRF5 autoriza associação a manejar cannabis com fins exclusivamente medicinais. https://www.trf5.jus.br/index.php/noticias/leitura-de-noticias?/id=324697 (accessed on 23/Apr/2023).
https://www.trf5.jus.br/index.php/notici... ; and compounding pharmacies were granted the right to make plant-derived preparations. According to the Judiciary, this would imply a trade restriction for foreign companies to manufacture cannabis-based products ¹⁴14. Consultor Jurídico. Juiz autoriza empresa a fabricar produtos derivados da cannabis. https://www.conjur.com.br/2023-dez-27/juiz-autoriza-empresa-a-fabricar-produtos-derivados-da-cannabis/ (accessed on 20/Apr/2023).
https://www.conjur.com.br/2023-dez-27/ju... . The arguments of bodies that are not technically prepared to act in health regulation divert the attention from the issues that need to be urgently resolved by Anvisa.

Today, the regulatory scenario for medical cannabis in Brazil has three categories: (i) Anvisa market-approved medicines, with only one example, a product containing synthetic cannabinoids; (ii) products authorized for manufacturing and sold in pharmacies, based on pure cannabidiol or cannabis extract, for which companies are only required to have a certificate of good manufacturing practices ⁵5. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 327, de 9 de dezembro de 2019. Dispõe sobre os procedimentos para a concessão da Autorização Sanitária para a fabricação e a importação, bem como estabelece requisitos para a comercialização, prescrição, a dispensação, o monitoramento e a fiscalização de produtos de Cannabis para fins medicinais, e dá outras providências. Diário Oficial da União 2019; 11 dec.. Around 30 products have a valid license ¹⁵15. Agência Nacional de Vigilância Sanitária. Consultas. Produtos de cannabis. https://consultas.anvisa.gov.br/#/cannabis/ (accessed on 20/Apr/2024).
https://consultas.anvisa.gov.br/#/cannab... ; and (iii) products with an import license that present a variety of cannabinoid compositions (full spectrum, broad spectrum, and isolate cannabinoid oils), in addition to different dosages forms (capsules, sublingual aerosols, patches, lotions, creams, and ointments), and concentrations ¹⁶16. Agência Nacional de Vigilância Sanitária. Nota Técnica nº 11/2024/SEI/COCIC/GPCON/DIRE5/ANVISA. Apresenta a lista de produtos derivados de Cannabis de que trata o §3o do Art. 5o da RDC no 660/2022. https://sei.anvisa.gov.br/sei/controlador_externo.php?acao=documento_conferir&codigo_verificador=2892303&codigo_crc=1001A4F1&hash_download=95cbfb5e38b4d3af92e3186b7670362806495393a3ad0e0597d520420807804165a930a53ab740000c38f6db12b21ed7ea0bda4fda06a33d1d81a264a7f9ff35&visualizacao=1&id_orgao_acesso_externo=0 (accessed on 22/Apr/2024).
https://sei.anvisa.gov.br/sei/controlado... . From 2015 to 2024, Anvisa published and updated about 30 lists of products with import authorization. The first list had 11 products ¹¹11. Agência Nacional de Vigilância Sanitária. Resolução RDC nº 17, de 6 de maio de 2015. Define os critérios e os procedimentos para a importação, em caráter de excepcionalidade, de produto à base de canabidiol em associação com outros canabinoides, por pessoa física, para uso próprio, mediante prescrição de profissional legalmente habilitado, para tratamento de saúde. Diário Oficial da União 2015; 8 may., and the most recent list, 582 ¹⁶16. Agência Nacional de Vigilância Sanitária. Nota Técnica nº 11/2024/SEI/COCIC/GPCON/DIRE5/ANVISA. Apresenta a lista de produtos derivados de Cannabis de que trata o §3o do Art. 5o da RDC no 660/2022. https://sei.anvisa.gov.br/sei/controlador_externo.php?acao=documento_conferir&codigo_verificador=2892303&codigo_crc=1001A4F1&hash_download=95cbfb5e38b4d3af92e3186b7670362806495393a3ad0e0597d520420807804165a930a53ab740000c38f6db12b21ed7ea0bda4fda06a33d1d81a264a7f9ff35&visualizacao=1&id_orgao_acesso_externo=0 (accessed on 22/Apr/2024).
https://sei.anvisa.gov.br/sei/controlado... . From 2015 to mid-2023, around 270,000 import authorizations were granted by Anvisa, allowing patients to obtain such products ¹1. Kaya Mind. Anuário da cannabis medicinal no Brasil 2023. https://kayamind.com/anuario-da-cannabis-medicinal-no-brasil-2023/ (accessed on 20/Apr/2023).
https://kayamind.com/anuario-da-cannabis... .

Growing demand and inadequate regulation are complemented by the low quality of evidence for most potential indications for using cannabis-based products. The effects of synthetic or natural cannabinoids on chronic pain, spasticity, nausea/vomiting, loss of appetite, amyotrophic lateral sclerosis, irritable bowel syndrome, multiple sclerosis, Huntington’s chorea, epilepsy, dystonia, Parkinson’s disease, glaucoma, attention deficit hyperactivity disorder, anorexia nervosa, anxiety, autism, dementia, depression, schizophrenia, post-traumatic stress, sleep disorders, drug addiction, Tourette’s syndrome, among others, have been studied in recent years. However, only a few indications have a high or moderate level of evidence ¹⁷17. Kelly LE, Rieder MJ, Finkelstein Y. Medical cannabis for children: evidence and recommendations. Paediatr Child Health 2024; 29:104-21..

For cannabidiol, the level of evidence was high for epilepsy and moderate for Parkinson’s disease. Moderate evidence was found for nabiximol for chronic pain, spasticity, sleep, depression, and drug addiction; and moderate evidence was observed for dronabinol for chronic pain, loss of appetite, and Tourette’s syndrome ¹⁷17. Kelly LE, Rieder MJ, Finkelstein Y. Medical cannabis for children: evidence and recommendations. Paediatr Child Health 2024; 29:104-21.. Studies are ongoing for other indications and the available evidence is insufficient ¹⁸18. Bilbao A, Spanagel R. Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications. BMC Med 2022; 20:259.^,1919. Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J. Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review. BMC Psychiatry 2020; 20:24..

The issue of safety

According to the Brazilian health legislation, no product for medical use can be manufactured, sold or delivered for consumption until it has been registered ²⁰20. Brasil. Decreto nº 79.094, de 05 de janeiro de 1977. Regulamenta a Lei nº 6.360 de 23 de setembro de 1976, que submete a sistema de vigilância sanitária os medicamentos, insumos farmacêuticos, drogas, correlatos, cosméticos, produtos de higiene, saneantes e outros. Diário Oficial da União 1977; 7 jan.. Despite the creation of a specific category, these products should comply with health regulations. After a post-approval 5-year period, products authorized for manufacture and sale must be registered with Anvisa. Until then, manufacturers, prescribers, and patients are responsible for the risks - in this case, the patients must sign an informed consent form. This creates a context of possible information asymmetry that could lead to a higher burden for patients.

But what about the number of products authorized for import? There is no registration planned for these products. Will the almost 600 products in this category continue to rely on fragile or even non-existent regulatory requirements that are currently in force? This situation favors individuals who obtain products through their own resources or through the courts. Litigation for access to products, fueled by social pressure, is made tense due to the relative lack of evidence and legal uncertainty, given that these products are not medicines. The actions of CONITEC (the Brazilian National Commission for the Incorporation of Technology into the SUS) are essential to address this issue in favor of the sustainability of the SUS.

The therapeutic use of an active ingredient depends on proof of efficacy and safety for a given indication. Adverse events of medical cannabis, as well as evidence of efficacy, have not yet presented conclusive results. A moderate association has been observed for the risk of adverse events with nabilone, nabiximol and CBD ¹⁷17. Kelly LE, Rieder MJ, Finkelstein Y. Medical cannabis for children: evidence and recommendations. Paediatr Child Health 2024; 29:104-21.. Cardiovascular, psychiatric, gastrointestinal and immune system events have been reported in the literature ²¹21. Solmi M, De Toffol M, Kim JY, Choi MJ, Stubbs B, Thompson T, et al. Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies. BMJ 2023; 382:e072348.. With THC-containing products, the patient may suffer disorders such as psychosis, related either to THC concentration or to chronic use, or addiction-like disorders, which are more severe in susceptible patients ¹⁹19. Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J. Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review. BMC Psychiatry 2020; 20:24.^,2121. Solmi M, De Toffol M, Kim JY, Choi MJ, Stubbs B, Thompson T, et al. Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies. BMJ 2023; 382:e072348.^,2222. MacCallum CA, Lo LA, Boivin M. "Is medical cannabis safe for my patients?" A practical review of cannabis safety considerations. Eur J Intern Med 2021; 89:10-8.^,2323. Zeraatkar D, Cooper MA, Agarwal A, Vernooij RWM, Leung G, Loniewski K, et al. Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: a systematic review of non-randomised studies. BMJ Open 2022; 12:e054282..

In the United States, in the debate on the regulation of medical cannabis, the issue of safety has focused on limited information on adverse effects of approved products, indicating the importance of conducting clinical trials ²⁴23. Zeraatkar D, Cooper MA, Agarwal A, Vernooij RWM, Leung G, Loniewski K, et al. Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: a systematic review of non-randomised studies. BMJ Open 2022; 12:e054282..

In Brazil, monitoring of adverse events requires Anvisa to encourage prescribers and patients to report such events, with the coordination of professional councils to protect patients and ensure evidence-based indications.

Who shapes regulation?

Although contributions from society help shape regulation, regulatory gaps pave the way for a market that is not always aligned with the interests of health. The result is a gradual increase in the number of companies seeking to operate in this niche, which is both lucrative and permeable.

Anvisa creates alternatives to make cannabis-containing products, which are not medicines and, therefore, have not been evaluated regarding efficacy, safety or quality, available to patients by means of a prescription only. In this case, the provision by the SUS of products that do not meet or do not comply with the health standards established in the legislation is even more serious.

Anvisa is expected to take a more assertive position regarding the regulation of cannabis for the indicated uses according to the evidence and the availability of products authorized for import and sale in the country. Anvisa has historically shown its determination to protect the Brazilian population; for example, when handling the COVID-19 pandemic. The same position is expected in the regulation of the cannabis market, as well as other relevant markets that affect the health of the population.

References

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