Throughout the development of the project, we actively sought the involvement of different sectors of society, ensuring that our results not only meet technical and scientific demands but are also socially relevant. In this context, engagement with various audiences, such as healthcare professionals, patient associations, and legal representatives, provided valuable feedback that shaped the direction of the project. Moreover, our commitment to understanding the social and regulatory impacts of synthetic CBD production in Brazil has been crucial in ensuring long-term viability, both in the market and in public policy.

Our approach encompasses strategic connections with academia, the community, industry, and government, building an integrated and sustainable project. Based on these interactions, we have adapted our scientific development to better meet the real needs of society, contributing to the advancement of knowledge and facilitating access to treatments based on synthetic CBD.

ACADEMIA

To fully understand the academic impact of the CBDynamics project, it’s essential to consider both the global and, more specifically, the Brazilian context in which the project is being developed. The use of cannabidiol-based medications faces significant challenges due to a lack of clear regulations and recognition from professional bodies, which in turn limits patient access to treatment and affects their overall well-being.

From this perspective, after intense internal discussions assessing the project’s feasibility, we recognized the importance of presenting this study to the academic community. There are many patients in need of this type of treatment, and demonstrating alternative ways to make it accessible can open up new avenues of research. This not only broadens scientific understanding but also challenges preconceptions and gaps in knowledge, encouraging the academic community to explore innovative solutions.

Furthermore, knowing the importance of the Academy for society, which is to promote the expansion of knowledge, that is, encouraging innovative projects in favor of a better quality of life for people. From this bias, our work seeks to boost Brazil's standing in research and innovative scientific production that favors future research and techniques, making them more accessible and viable. Moreover, thinking about contributing to this dissemination, our Human Practices team disseminated the knowledge we've gained in molecular biology to the local and virtual community, through social networks and educational events.

Over the past two years, our efforts to validate and refine the project have included numerous consultations with experts, yielding valuable insights. These specialists have rigorously assessed our methodologies in areas such as modeling, reactor specifications, and laboratory workflows, offering constructive feedback on enhancements, corrections, and commendations. This collaborative process has enabled us to make critical improvements, strengthening the academic significance of the project. Through continuous persistence and teamwork, we have established a robust foundation for future research that will not only advance the field of synthetic biology but also enhance the accessibility of CBD-based treatments.

It can be inferred, therefore, that the academic sector is directly impacted by the potential of CBDynamics. Given the bureaucratic hurdles surrounding access to treatment, it is evident that academia has a crucial role in advancing alternative studies and promoting new research in synthetic biology to address these challenges. By doing so, academic institutions can contribute to overcoming barriers and ultimately help improve the well-being of the population through more accessible and innovative solutions.

Therefore, to emphasize the progress made in our project and strengthen our connection with the scientific community, we actively pursue participation in national and international conferences and events. These platforms allow us to share and discuss our most recent advancements, fostering collaboration and promoting further development of our research.

3RD CONGRESS & 3RD INTERNATIONAL MEETING ON AUTISM SPECTRUM DISORDER

In 2023, we had the unique opportunity to collaborate with Professor José Otavio Motta Pompeu e Silva from the Federal University of Rio de Janeiro, an autistic researcher interested in the use of cannabidiol (CBD) to treat autism symptoms. As part of that collaboration, we were invited to present the impact of our project during a live YouTube session on his channel, “Espaço Alexandria - #REDEAUTISMO”. See more in (our 2023 collab).

This year, in partnership with Professor José and the Caminho Azul Association, we participated in the "3rd Congress & 3rd International Meeting on Autism Spectrum Disorder: Filling the Gaps ‘TOP DOWN’ and ‘BOTTOM UP’" at Federal Fluminense University. At this conference, we attended various sessions, lectures, and workshops focused on autism and the need for alternative treatments. Our team was also invited to discuss the relevance of our project on the official congress podcast, hosted by Professor José, which was published on YouTube and received overwhelmingly positive feedback. Additionally, our research was showcased during the congress poster session, further reinforcing the significance of our work. Through events like these, we aim to bridge the gap between academia and society, demonstrating how synthetic biology can drive innovation in healthcare and beyond.

1ST BRAZILIAN CONGRESS OF SYNTHETIC BIOLOGY

Our active participation in the 1st Brazilian Congress of Synthetic Biology (CBBS), organized by the Brazilian Synthetic Biology Association (SynBioBR) and the SENAI Institute of Innovation (ISI), showcased the recent advances in our project through a poster presentation. This event not only highlighted our research but also allowed us to build connections within the Brazilian synthetic biology community. It provided an invaluable platform for engaging in discussions on the latest scientific and technological developments in synthetic biology, alongside peers from universities across the country.

iGEM LATAM MeetUp

At the iGEM LATAM MeetUp, organized by the iGEM Tec CEM team from Mexico, we had the opportunity to present our project, sharing our team's achievements. In addition to our presentation, we attended sessions from other iGEM teams, gaining insights into the innovative projects emerging from various countries in Latin America this year. We were inspired by the diverse and innovative projects presented by other iGEM teams from across Latin America. During the Q&A sessions following our presentation, we received valuable feedback that encouraged us to enhance our project and provided insights for the project refinement.

FUTURE PRESENTATIONS

Our involvement in these significant events not only allowed us to showcase our work but also strengthened our commitment to advancing synthetic biology. Still this year, we will soon be presenting a local event at our campus, the XIV Industrial Biotechnology Week, organized by Academic Center for Biochemical Engineering (CAEB), to share our project's latest developments with our university. This event will provide an in-depth look at the CBDynamics project, offering students and researchers the chance to engage with our research and discuss its broader implications in engineering.

In addition, we have been invited to present on the SynBioBR YouTube channel, at the “SynBioBR Convida”, which aims to disseminate knowledge in synthetic biology and celebrate the work of Brazilian professionals in the academic, industrial and entrepreneurial fields. This platform will enable us to reach a wider audience more specifically in synthetic biology, where we will delve into the technical details and future directions of our project.

LOCAL COMMUNITY

In this second year of research, we have achieved even more significant impacts on society. CBDynamics goes beyond merely innovating a synthetic cannabinoid-based drug; our objective is also to understand and positively influence the local community while promoting inclusivity and engagement. See more of Inclusivity here.

Throughout our interactions with various societal groups, we gained valuable insights into the challenges faced by individuals in need of cannabidiol. This understanding has enabled us to tailor our efforts to better assist these individuals based on the diverse feedback we received.

While academic recognition from industry, government, and public organizations is crucial, the acceptance and support of the local community are equally essential for the success of the CBDynamics project. The stories and experiences shared with us underscore the urgent need to enhance access to CBD-based treatments, particularly for those confronting financial and logistical barriers.

Our work has been a catalyst for broader discussions on the medicinal use of CBD, challenging historical stereotypes and prejudices. By challenging the persistent stigmas surrounding Cannabis, our proposal for synthetic cannabidiol production seeks to raise awareness about the legitimacy of medicinal cannabis use. The CBDynamics project directly addresses this issue by providing a synthetic alternative to cannabidiol, which helps demystify cannabis and separates its medicinal applications from historical prejudices. Through educational and awareness initiatives highlighting the benefits of CBD, the project actively works to dismantle negative stereotypes and promote social justice, ensuring that everyone has access to safe and effective treatments.

Following this line, in the first semester of 2024, our team collaborated with the social organization “Idoso Amigo”, organized by students from the School of Engineering of Lorena, which promotes the connection between young people and the elderly and improves the quality of life for seniors in shelters. During the event, we had direct contact with several caregivers, who proved to be very attentive and dedicated in their roles. Considering that some diseases treated with CBD frequently affect the elderly population, we saw an opportunity to better understand the effects of our project on the local community.

With this in mind, we reached out to one of the caregivers, Aline Albres to explain our project and, additionally, to collect data to better understand her experience. The results of this collection are presented below:

Aline Albres - caregiver at Vila Vicentina nursing home

1. How is it to deal daily with elderly individuals suffering from Alzheimer in the nursing home?
   “It is quite exhausting. The nursing home cares for 43 elderly individuals, most of whom have Alzheimer or dementia. Some use CBD, which their families pay for, but most cannot afford it or refuse to use CBD for treatment due to prejudice. In my brother's case, his Alzheimer stabilized with the use of CBD – 10 drops in the morning and 10 at night. We spent over a thousand reais on this treatment, in addition to private consultations and other expenses.”
2. What types of challenges or specific symptoms do Alzheimer’s patients regularly face?
   “One example of a patient with severe symptoms is Maria José, 86 years old, who wouldn’t eat, was aggressive, and is in the final stage. However, after about 45 days of treatment, she stopped having spasms and began to understand what we say, in addition to starting to eat again. She discovered CBD when she started using it to relieve the pain caused by leukemia.”
3. What are your expectations regarding the results of this therapeutic project?
   “They will have more access with the reduction of costs, considering that many receive only a minimum wage. My family can afford to buy it, but some cannot. One of the patients, for example, suffers from anxiety attacks, and the nursing home cannot cover that purchase every month.”
4. How do you think the relatives of the elderly would react to the implementation of a therapeutic project with synthetic cannabidiol?
   “I believe the family would not accept it due to the stigma surrounding the plant.”
5. How do you evaluate the overall acceptance of the elderly regarding new therapeutic approaches like this?
   “Elderly individuals with Alzheimer do not know what is happening, so this decision would entirely fall to the family, which, as I said, is not very open to these initiatives.”

After the data collection, it became evident the significant potential of CBDynamics to transform the lives of thousands of people. This innovation is especially promising for the elderly population, whose quality of life could be considerably improved if they had access to this treatment. Unfortunately, in the current reality of the country, this access is still not universal, limiting opportunities for many individuals who could benefit immensely, both for financial and social reasons. Therefore, expanding the availability of CBDynamics could not only offer relief and improve the health of the elderly but also represent an important advancement in equity and acceptance in access to innovative treatments.

PUBLIC ASSOCIATIONS

In Brazil, non-governmental organizations play a critical role in disseminating information and fostering connections between CBD treatments, medical professionals, and patients. These associations, dedicated to modern solutions that prioritize patient well-being, serve as vital bridges in promoting awareness and access to CBD-based therapies.

This year, we engaged with organizations such as the Luso-Brazilian Association of Cannabis Nursing (ALBECAN) and the Santa Erva Association to gather valuable data and constructive feedback. These interactions took place via Google Meet, where we introduced and presented our project, outlining its potential impact on their sectors and gathering their insights and suggestions.

The Santa Erva Cannabis Association and the Luso-Brazilian Association of Cannabis Nursing (ALBECAN) both play pivotal roles in promoting the medicinal use of cannabis. Santa Erva focuses on educating the public and raising awareness about the therapeutic benefits of cannabis, while also providing essential support to patients in need of cannabis-based treatments. In parallel, ALBECAN is dedicated to the therapeutic application of cannabidiol (CBD) and other cannabis derivatives in nursing, aiming to enhance patient care by offering education and guidance to healthcare professionals. Both organizations advocate for scientific research and support the development of public policies to advance the medicinal use of cannabis, ensuring that patients and professionals alike have access to reliable, up-to-date information. Together, they contribute to the humanization and destigmatization of cannabis use in healthcare, while promoting its benefits for patient well-being.

It is worth highlighting the meeting that took place on July 4th, where the USP-EEL-Brazil team held a meeting with the Santa Erva Cannabis Association and ALBECAN, the Luso-Brazilian Cannabis Nursing Association. This collaboration aimed to discuss improvements for our project, collect testimonials from patients who use cannabidiol, and obtain guidance from doctors on important topics for the development of our work.

The meeting began with the team's presentation to the association, where we detailed the CBDynamics project. Then, we received feedback about our project, and they expressed enthusiasm for the innovative idea. Furthermore, they pointed out some areas for improvement that we could include from a social perspective.

One of the key questions raised by the team was why we chose cannabidiol over other cannabinoids. Both organizations expressed the importance of other cannabis derivatives and suggested we consider studying them as well, since these compounds are often administered together to achieve satisfactory results. We explained that cannabidiol is the most suitable option due to its research feasibility, legal considerations, and overall accessibility. In light of this, we pointed out that the synthetic pathway for other components like THC, for example, was quite similar to that of cannabidiol. Additionally, we highlighted that, within the context of our project, using Saccharomyces cerevisiae yeast is crucial, since it is not only easily accessible but also manageable, which significantly facilitates the production of this compound. Furthermore, our research and the biological circuits we develop can serve as a foundation for future studies focused on the production of other cannabinoids.

As organizations dedicated to promoting the medicinal use of cannabinoids, they raised a pertinent concern regarding the prevailing prejudice against synthetic production in society. In response, we clarified that synthetic biology is experiencing significant growth and is a promising field that adheres to rigorous biosafety protocols, ensuring legitimacy and safe, controlled production. Since the project's inception, our team has been committed to dismantling the stigma surrounding cannabis, striving to present this topic in an informative and clear manner for public understanding. Additionally, to understand the community’s perception of our project, we conducted a data collection in 2023, yielding very positive results, which you can find at this link. This last year's studies focus on a national perspective, aiming to develop a project to improve accessibility and quality of life in Brazil. However, during the meeting, the question arose regarding other countries, and having an external perspective could expand and detail our project in a way that had not been previously explored.

To respond to this feedback, we conducted extensive research to understand if and how other countries have approached the issues of stigma and acceptance of synthetic phytocannabinoid medications. To exemplify the aforementioned question, we noted that several countries already utilize the synthetic production of cannabinoid-based drugs, such as Epidiolex® (Cannabidiol), Marinol® (Dronabinol), Cesamet® (Nabilone), and Sativex® (Nabiximols).

The following is a compilation of pertinent data regarding each drug cited:

Marinol® (Dronabinol)

Marinol® is a synthetic form of THC used to treat nausea and vomiting caused by chemotherapy and appetite loss in HIV/AIDS patients. It works by stimulating appetite and reducing nausea by interacting with cannabinoid receptors in the brain. (FDA, 2023)

Cesamet® (Nabilone)

Cesamet® contains nabilone, a synthetic analogue of THC, primarily used to treat severe nausea and vomiting in patients undergoing chemotherapy. It is administered when conventional treatments are ineffective (MHRA, n.d.).

Sativex® (Nabiximols)

Sativex® is an oral spray containing THC and CBD, used to alleviate spasticity in multiple sclerosis patients. It may also be effective in treating neuropathic pain. It is approved in many countries but not in the US (EMA, n.d.).

Epidiolex® (Cannabidiol)

Epidiolex® is a CBD-based medication approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. It is the first cannabis-based drug approved by the FDA in the US (FDA, 2023).

Above, we discussed several cannabinoid-based pharmaceuticals. In this section, we will delve deeper into some of them. Initially, we have Marinol® and Cesamet®, both composed of THC and its synthetic analogs, used to treat chemotherapy-induced nausea and vomiting, and appetite loss in HIV/AIDS patients. Epidiolex® is a CBD-based medication approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Additionally, Sativex® is an oral spray containing both THC and CBD. It is used to alleviate spasticity in multiple sclerosis patients and may also be effective in treating neuropathic pain.

Therefore, it can be concluded that many of these medications are primarily utilized only when conventional treatments prove ineffective, reaffirming the necessity to demystify this pharmaceutical branch. Moreover,it is noteworthy that CBD is administered in conjunction with THC in certain medications, such as Sativex®, suggesting that it could be advantageous to produce both cannabinoids, given the more significant impact of their combined efficacy and the similarity of their synthetic pathways.

The global recognition of cannabinoids, evidenced by the acceptance of these medications in various countries, indicates that the CBDynamics project is well-positioned to make a significant contribution to the field of cannabinoid-based medicine. However, it is essential to highlight that the acceptance and success of the project depend on the strict adherence to approval criteria. Our team is committed to gathering all necessary information to meet these requirements, aiming to enhance the project's market position while expanding its potential for social impact and international success.

While some countries maintain restrictive legislation regarding cannabinoids is extremely restrictive, a noticeable trend is emerging in the global market. This can be categorized into three distinct approaches, influenced by the intensity of stigma in the location. In some countries, CBD is still surrounded by prejudice and denial, and local policies reflect this, with rigid prohibitions that do not distinguish medicinal use. In others, although stigma is still structured in society, it has been combated through scientific evidence, making CBD-based medications increasingly accepted. Finally, the last one demonstrates an inspiring and innovative example, as it recognizes the differences between recreational and medicinal use and supports the therapeutic aspect to treat patients who benefit from this medication.

Therefore, we reaffirm the importance of education and inclusion, since informing the population and bringing information to individuals and those inserted in a stigmatized collective thought is fundamental for ideological barriers to be overcome and issues such as the one we are addressing to be normalized, so that there is more research, development and evolution in areas which have the capacity to change many lives.

In addition to the recognition in academia, industry and government, the acceptance and support of the local community is fundamental to the success of the CBDynamics project. The stories and experiences shared with us highlight the urgency of expanding access to CBD-based treatments, especially for those facing financial and logistical barriers. Our work has been a catalyst for broader discussions about the medicinal use of CBD, challenging historical stereotypes and prejudices.

GOVERNMENT

The journey of CBD regulation in Brazil can be exemplified by some crucial initiatives:

In December 2019, the National Health Surveillance Agency (ANVISA) published Collegiate Board Resolution (RDC) 327/2019. This resolution established the requirements for the regulation of cannabis products for medical purposes in Brazil, allowing the manufacture, importation, and commercialization of cannabis-based products under medical prescription. RDC 327/2019 was a significant milestone, as it provided a clear and safe regulatory pathway for companies and patients, fostering the development of a regulated market for cannabis products in the country.

In November 2023, the state of São Paulo took a significant step forward by enacting Law No. 17,618. This law authorized the Unified Health System (SUS) within the state to provide cannabis-derived medications to patients with medical prescriptions. The measure was met with optimism, as it expanded access to treatments that can be fundamental for patients with severe conditions who do not respond well to conventional therapies.

At the national level, Bill No. 89/2023, currently under consideration, represents a significant advancement in public health policy regarding cannabinoids. This bill aims to guarantee the availability of cannabinoid-based medications through the Unified Health System (SUS) throughout the country, not only in the state of São Paulo. If approved, Bill No. 89/2023 could expand access to treatments, promoting equity in the provision of CBD-based therapies and other cannabinoids for all Brazilians in need.

We can observe that the government is increasingly adopting a more receptive stance towards medical CBD. However, these changes have thus far been fully embraced only in certain regions of the country, highlighting the importance of awareness-raising and the informative work of the project.

Beyond collecting data from last year's form, we revisited the responses to reflect on public opinion regarding the project. The feedback from our university members was overwhelmingly positive. However, one comment caught our particular attention: 'I believe this would be analogous to the legalization of marijuana' highlighting a knowledge gap among some individuals regarding the distinction between recreational and medicinal use. Recognizing the complexity of the topic and the diversity of opinions surrounding it, we understand the importance of considering different perspectives. In light of this, we have decided to refocus our project and clarify its objectives, given the controversy surrounding the topic, it is essential to provide clear interpretations.

Therefore, we contacted a judge and a federal prosecutor to gain a deeper understanding of the legal nuances involved in the following text, clarifying any doubts we may have. Below are some key responses from our interviews:

1. In your opinion, would the use of synthetic cannabidiol be analogous to the legalization of marijuana?

Answer: “However, it could be used as an ideological banner to achieve the unrestricted legalization of marijuana for all purposes. A cultural shift is needed to differentiate between medicinal and therapeutic use and the so-called 'recreational' use of the substance.”

1. It is commonly heard that some people are using medicinal cannabidiol as a means to legalize recreational use, but we believe these two uses are distinct. Does the law also distinguish between these two uses?

Answer: “Yes. The recreational use of marijuana is still considered a crime in Brazil. On the other hand, the use of synthetic cannabidiol is currently permitted under the Ministry of Health's Ordinance SVS/MS No. 344 of May 12, 1998, which removes it from the category of illegal substances.”

1. Have you heard about cases of people who had to go to court to be allowed to use cannabidiol? Is this process of obtaining it still bureaucratic and difficult to access?

Answer: “Yes, the cases are not so rare and the process, to be honest, is simple, but it requires the recruitment of a technical professional (lawyer, public defender, etc.), an unfamiliar situation, in general, for the population. In addition, there is no guarantee that the person will be able to access cannabidiol through a lawsuit, everything varies according to the case.“

1. Regarding our project, what is your opinion about it being someone in the area of Law? Would the project help society in the legal part?

Answer: “Projects like this help, if well conducted, to break down a psychological barrier that still exists in many, and may lead to a wider and less bureaucratic distribution of synthetic cannabidiol-based drugs in the future. However, it is always necessary to avoid the ideological use of actions like these, as this could lead to the disastrous effect of facilitating the unrestricted legalization of marijuana, with consequences that no one can yet measure.”

1. Many patients complain about Anvisa's long waiting times and all its bureaucracy in relation to cannabidiol. What is your opinion on this?

Answer: “I think that, as the therapeutic use of cannabidiol proves to be beneficial, these bureaucracies tend to be lifted. There is still a lot of social controversy involving the subject precisely because of the ideological division it causes.”

1. What are the future prospects for the regulation and use of synthetic cannabidiol in the Brazilian legal scenario? Do you believe that projects like this can help in this process?

Answer: “Strictly speaking, this use is already regulated, even though the restrictions are great... Any project in this sense is valid and should be praised, always taking care to draw a dividing line between the medicinal – and, therefore, good – use of any substance and its use as a narcotic. That is the great challenge.”

Such authoritative responses underscore the relevance and quality of our project, which adheres to all legal nuances, providing validation and encouragement to move forward with confidence.

Recent government initiatives indicate a significant shift toward the acceptance and regulation of therapeutic Cannabis use, reflecting both international trends and robust scientific evidence supporting the efficacy of CBD in treating various medical conditions. A key advantage of synthetic CBD production is that it facilitates the independent manufacture of medications, offering a reliable alternative to traditional extraction methods, which may be subject to ideological biases.

HEALTH SURVEILLANCE

Reflecting on our meeting with the ALBECAN and Santa Erva associations, we received valuable feedback regarding how observing the international context of synthetic cannabinoids could inform our proposals for change and help combat the stigma surrounding CBD. A notable insight emerged from our research into synthetic drugs and their status abroad, is that Epidiolex® was the first CBD-derived medicine approved by the U.S. Food and Drug Administration (FDA) and has since gained approval in several countries with more stringent regulations. In light of this, we compared the evaluation processes of the FDA and Anvisa to identify potential bureaucratic differences between the two regulatory bodies. Our initial focus was to examine the standard procedures for drug approval, considering the general requirements that apply uniformly to all drugs.

FDA (Food and Drug Administration, 2024)

1. Initial Submission:

Companies must submit an IND (Investigational New Drug Application) to start clinical trials.

2. Clinical Trials:

They go through rigorous phases of clinical trials (Phase 1 to 3), assessing safety, efficacy and dosage.

3. Review:

After the trials, they submit an NDA (New Drug Application) for full review.

4. Approval:

Final review includes manufacturing inspections and analysis of complete clinical trial data.

5. Post-Market Monitoring:

Approved products are continuously monitored for adverse effects.

Anvisa (National Health Surveillance Agency, 2024)

1. Initial Submission:

Companies must submit an Application Subject to start clinical trials.

2. Clinical Trials:

They carry out clinical trials in three phases, with specific protocols approved by Anvisa.

3. Review:

After trials, companies submit a Drug Clinical Development Dossier (DDCM) containing data from the clinical studies.

4. Approval:

Anvisa reviews the DDCM, including manufacturing inspections and complete clinical trial data.

5. Post-market monitoring:

Approved products are continuously monitored for safety and efficacy.

We then analyze the approval protocol, specifically for cannabidiol products, in order to see if there are any incentives or bureaucratic hurdles involved for these classes, in addition to the official protocol.

U.S. Food and Drug Administration (FDA)

The protocol for CBD medicines, with THC content below 0.2%, follows the same regulatory rigor as any other medicine. In the case of Epidiolex®, its efficacy was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex®, taken together with other medicines, has been shown to be effective in reducing the frequency of seizures when compared with placebo. It does not have such a detailed specific regulation for CBD as Anvisa, but it strictly monitors the safety and efficacy of approved products.

In addition, the agency has a policy of supporting scientific research, assisting the development of medicines in this area through:

Providing information on the process required to conduct clinical research using cannabis.

Providing information on the specific requirements needed to develop a human medicine derived from a plant such as cannabis. InDecember 2016, the FDA updated its Guidance for Industry: Botanical Drug Development, which provides sponsors with guidance on how to submit investigational new drug (IND) applications for botanical drug products. The FDA also issued "Cannabis andCannabis-Derived Compounds: Quality Considerations for ClinicalResearch, Draft Guidance for Industry."

Providing specific support for researchers interested in conducting clinical research using cannabis and its constituents as part of theIND or investigational new animal drug (INAD) process through regular meetings and interactions throughout the drug development process.

Providing general support to researchers to help them understand and follow procedures for conducting clinical research through theSmall Business and Industry Assistance group of the FDA's Center For Drug Evaluation and Research (CDER).

National Health Surveillance Agency (Anvisa)

Anvisa has specific regulations for CBD drugs, with the application of RDC 327/2019, aimed at marketing, production and importation, and RDC 660/2022, more focused on imports, requiring additional requirements for Cannabis products, such as:

Specific operating authorization (AFE) for companies that produce or import cannabis-based products.

Good Manufacturing Practices (GMP) and strict quality controls. Products should be labeled with specific information about cannabinoid concentration and warnings for use.

The importation for personal use of CBD products requires a medical prescription and prior authorization from Anvisa.

This comparison highlights that the FDA adopts a less bureaucratic approach to CBD regulation compared to Anvisa. Despite this, the FDA's protocols, clinical trials, and market monitoring effectively ensure quality and safety for consumers. Furthermore, the FDA promotes robust scientific research, fostering a collaborative environment conducive to future research and development. In contrast, our analysis of the Brazilian regulatory framework reveals a lack of incentives and an overly cautious stance from the government, which may hinder national production efforts and increase dependence on imports in the cannabinoid sector.

The approval process by regulatory agencies is significantly influenced by prevailing legislation. Thus, this lack of governmental incentive manifests not only in legal barriers but also in vague provisions and gaps within current laws. In light of the bureaucratic obstacles we face and our commitment to making cannabidiol more accessible, by actively participating in shaping public policies that streamline the approval of CBD, we can enhance transparency and fairness in the regulatory process. To do so, we began researching proposed laws currently under consideration to ensure compliance with existing legislation and address the regulatory gaps surrounding our project.

SECURITY

In line with our commitment to caution and responsibility, we have closely examined the regulations governing medicines, drugs, pharmaceutical inputs, and related substances. Below, we outline the key provisions of Law No. 6,360, enacted on September 23, 1976, that are relevant to this context.

´´Article 2 - Only companies authorized by the Ministry of Health and whose establishments have been licensed by the health agency of the Federative Units in which they are located may extract, produce, manufacture, transform, synthesize, purify, fractionate, pack, repackage, import, export, store or ship the products referred to in Article 1.´´

It is important to note that if our project successfully transitions into a drug, it will require approval from the Ministry of Health. Until that point, we are strictly adhering to the relevant research protocols as outlined in "Safety."

´´Art. 13 - Any modification of the formula, alteration of the elements of composition or its quantities, addition, subtraction or innovations introduced in the preparation of the product, shall depend on priorand express authorization from the Ministry of Health and shall be immediately recorded in the registration.´´

´´Art. 15 - The registration of the products referred to in this Law shall be denied whenever the conditions, requirements and procedures for such purpose provided for in the Law, regulation or instruction of the competent body are not met.´´

´´Article 16. The registration of drugs, medicines, pharmaceutical inputs and related products, given their sanitary, medication or prophylactic, curative, palliative, or even for diagnostic purposes, is subject, in addition to meeting the requirements themselves, to the following specific requirements: (Law nº 10.742, de 6.10.2003)

I - that the product complies with the provisions of article 5, and it 's paragraphs. (Redação dada pelo Decreto nº 6.480, de 1.12.1977)

II - that the product, through scientific proof and analysis, is recognized as safe and effective for the use for which it is proposed, and has the necessary identity, activity, quality, purity and harmlessness;

III - in the case of a new product, that ample information be offered about its composition and use, in order to evaluate its nature and determine the degree of safety and efficacy necessary;

IV - presentation, when requested, of a sample for analyses and experiments that are deemed necessary by the competent bodies of the Ministry of Health;

V - when there is a new substance in the composition of the drug, delivery of a sample accompanied by chemical and physical-chemical data that identify it;

VI – in the case of drugs or medicines whose elaboration requires technical and specific equipment, proof that the establishment is properly equipped and maintains personnel qualified to handle it or contract with third parties for this purpose.

VII – the presentation of the following economic information: (Law nº 10.742, de 6.10.2003)

a) the price of the product practiced by the company in other countries; (Law nº 10.742, de 6.10.2003)

b) the acquisition value of the active substance of the product; (Law nº 10.742, de 6.10.2003)

c) the cost of treatment per patient with the use of the product; (Law nº 10.742, de 6.10.2003)

d) the potential number of patients to be treated; (Law nº 10.742, de 6.10.2003)

e) the price list that it intends to practice in the domestic market, with a breakdown of its tax burden; (Law nº 10.742, de 6.10.2003)

f) the breakdown of the product's marketing proposal, including the expenses foreseen with the sales effort and with advertising and advertising; (Law nº 10.742, de 6.10.2003)

g) the price of the product that has undergone modification, in the case of a change in formula or form; and (Law nº 10.742, de 6.10.2003)

h) the list of all substitute products on the market, accompanied by their respective prices. (Law nº 10.742, de 6.10.2003)´´

Thus, as we look towards the future of our project, it is imperative that transparency and adherence to established standards remain foundational pillars of CBDynamics. This commitment underscores our dedication to ethical practices and compliance with legal regulations.

PRODUCTION

Knowing our responsibility to ensure the effectiveness and quality of our product, we sought information on the laboratory standards that concern the production of synthetic cannabidiol, which are present in Resolution No. 18, of March 23, 2018, of CTNBio.

With this collection of “[…] § 2º For activities with GMOs of Risk Classes 2, 3 and 4, CIBio must obtain authorization from CTNBio for each project and the information presented must be in accordance with the Authorization Request forActivities in Containment with GMOs and their derivatives, contained in Normative Resolution No. 1, and the detailed methodology for identifying the GMO must also be informed. Art. 5 After the activity is approved by CTNBio or CIBio, the institution's legal representative, CIBio and the main technician are responsible for ensuring faithful compliance with the biosafety standards defined by CTNBio.

[…]

§ 2º Every genetically modified organism must have a marker capable of identifying it among a population of the same species. II – Risk Class2 (moderate individual risk and low risk to the collectivity): GMOs that contain DNA/RNA sequences with moderate risk of harm to human and animal health, which have a low risk of dissemination and causing adverse effects to plants and the environment;

[…]

II – Biosafety Level 2 (NB-2): suitable for activities and projects involving GMOs of Risk Class 2, carried out under the following conditions:

a) the facilities and procedures required for NB-2 must meet the specifications established for NB-1, plus the need for an autoclave orother efficient decontamination system, available inside or near it, in a contiguous area, in order to allow the decontamination of all material before disposal, without the transit of the GMO through corridors and other uncontrolled spaces or with public access, It is also observed:

[…]

Art. 11 Activities and projects in containment involving cultivation or manipulation of GMOs on a large scale must follow the biosafety standards established in Chapter V of this Normative Resolution, plus the following containment measures:

I - in addition to the biological risks related to activities with GMOs and their derivatives on a large scale, the risks related to the toxicity of products and the physical, mechanical and chemical aspects of the production process must be considered in the adoption of appropriate containment and protection measures;

II - the institutions must maintain a health surveillance program for all workers who work in the facilities that maintain activities with GMOs;

III - clinical examinations must be annually; and

IV - Situations of potential risk should be described and clinical examinations should include indicators for long-term monitoring, such as the constitution of a serology bank with specific markers, when available, for epidemiological surveillance purposes, for research activities and projects involving genetically modified organisms belonging to Risk Class 2, 3 or 4.[…]”

PROPOSED BILL

After thoroughly analyzing the existing standards, we noted that the regulation of synthetic drugs for CBD has not been addressed in any current legislation. Therefore, to promote meaningful changes in public policy, we undertook extensive research and reflection, culminating in the development of a bill document aimed at filling the gaps in Brazilian law concerning synthetic CBD products.

To enhance the quality and relevance of this proposal, we collaborated with Paulo Aguiar Muniz, Director of Policy and Regulation at the Brazilian Association of Synthetic Biology (SynBioBR), who generously provided valuable insights and actively participated in the document's review process.

Our proposed bill holds considerable significance as it aims to establish a definitive distinction between synthetic CBD and CBD derived from Cannabis plants. This differentiation is essential for the formulation of regulatory frameworks that can endure political fluctuations, thereby ensuring reliable access to effective treatments for individuals in need.

After the development and revision of the proposed bill, the next steps for this project involve a series of strategic actions. Firstly, it will be essential to seek feedback from legal experts who can validate the content and suggest necessary adjustments. Engaging with relevant stakeholders, such as patient associations and synthetic biology organizations, will allow for the presentation of the project and the gathering of support. Concurrently, an advocacy strategy will be developed to promote the project among lawmakers, emphasizing its significance and the benefits of regulating the use of synthetic CBD. Meetings with political representatives and other interested parties will be organized to discuss the project and clarify any questions. Additionally, a public support mobilization campaign will be launched, utilizing social media and events to raise awareness of the proposal and encourage petition signing.

The formal presentation of the proposed document to the competent legislative body will be accompanied by the necessary documentation and a detailed justification of its relevance. Following the submission, it will be crucial to monitor the project's progress in the legislative chamber, participating in hearings and discussions to defend the proposal and adjust it based on the feedback received. Continuing to educate the public and stakeholders about the benefits of synthetic CBD and the need for regulation will also be a priority, utilizing research data and expert testimonies. Finally, ongoing evaluation and necessary adjustments will remain open to facilitate the acceptance and approval of the bill, ensuring that the desired regulation for the use of synthetic CBD in Brazil advances successfully.

INDUSTRY

Our synthetic cannabidiol development project is closely aligned with the emerging demands of the pharmaceutical and biotechnology industries. Utilizing biotechnology-based production methods offers a promising alternative to the traditional extraction of cannabinoids from plants, bringing several direct benefits to the industrial sector.

In Brazil, according to Anvisa (National Health Surveillance Agency), 25 cannabinoid-based medications are currently approved for sale, with the most recent being "Cannabidiol Aché," produced by ACHÉ LABORATÓRIOS FARMACÊUTICOS S.A., which was approved in April 2024. The increasing number of new market entries, particularly from national industries, demonstrates the growing potential of CBD and underscores the relevance of initiatives like ours.

The pharmaceutical industry operates under strict quality standards and bears significant responsibility to ensure consumer safety. As a result, we compiled the necessary requirements and obligations related to orally administered medications, which are outlined in the "Safety" section of our proposal.

Furthermore, recognizing the potential of synthetic cannabidiol to transform the industry, we actively sought input from key players in the biotechnology and pharmaceutical sectors. In our consultations with key industry players, we received valuable feedback that further validates our approach.

SINDUSFARMA (Pharmaceutical Products Industry Union) emphasized the industrial sector's concern regarding the quality and purity of cannabidiol-based compounds. They noted that since synthetic cannabidiol is produced in a controlled laboratory environment, it offers greater assurance of safety and consistency in the project's results. SINDUSFARMA advocates for the legal and corporate interests of Brazil's pharmaceutical industries, promoting their development while safeguarding public health and well-being.

Additionally, Braskem, a prominent petrochemical company, highlighted the economic feasibility of our project. They indicated that producing CBD via fermentation has the potential to be more cost-effective than extracting molecules from plants, reinforcing our project's viability in a competitive market.

Therefore, positioned at the forefront of synthetic biology, our project not only drives innovation in the market but also lays the groundwork for the emergence of new companies and solutions within the sector. Building on the analyses mentioned above and to enhance our connection with the industry and entrepreneurial landscape, our team has developed, in collaboration with Mona Oliveira, CEO of BioLinker, a comprehensive business model proposal. This model, detailed in the Business Proposal tab, complements and aligns with the objectives outlined in this text.

REFERENCES

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Brazil. (1976). Law No. 6,360, of September 23, 1976. Presidency of the Republic. https:// https://legi.pr.gov.b/a/?ti=LEI&numer=6&ano=1976&ato=f0eETQq50MnRVTe

Brasil. Senado Federal. (2023). Projeto de Lei nº 89, de 2023. Retrieved July 27, 2024, from https://www25.senado.leg.br/web/atividade/materias/-/materia/155747

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Conselho Federal de Farmácia. (2024, January 8). Medicamentos à base de cannabis estarão disponíveis para pacientes do SUS no estado de São Paulo. Retrieved from https://site.cff.org.br/noticia/Noticias-gerais/08/01/2024/medicamentos-a-base-de-cannabis-estarao-disponiveis-para-pacientes-do-sus-no-estado-de-sao-paulo#:~:text= Medicamentos%20%C3%A0%20base%20de%20cannabis,no%20estado%20de%20S%C3%A3o%20Paulo&text=Na%20% C3%BAltima%20semana%20de%202023,%C3%9Anico%20de%20Sa%C3%BAde%20(SUS)

CTNBio. (2018). Resolução Nº 18, de 23 de março de 2018. Retrieved September 27, 2024, from: https://ctnbio.mctic.gov.br/resolucoes-normativas/-/asset_publisher/OgW431Rs9dQ6/content/resolucao-n%C2%BA-18-de-23-de-marco-de-2018

European Medicines Agency (EMA). (n.d.). Sativex: European public assessment report. Retrieved from https://www.ema.europa.eu

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Ministério da Saúde. (2022). Resolução RDC n° 660, de 30 de março de 2022. Diário Oficial da União: Seção 1. Retrieved July 27, 2024, from https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-660-de-30-de-marco-de-2022-389908959

MHRA. (n.d.). Cesamet (Nabilone) information. Retrieved August 1, 2024, from https://www.gov.uk

National Health Surveillance Agency. (2019). Collegiate Board Resolution – RDC nº 327, of December 9, 2019 (RDC nº 327/2019). Brasília, DF.

National Health Surveillance Agency. (n.d.). Consultas públicas: Cannabis (nº 25722). Retrieved from https://consultas.anvisa.gov.br/#/cannabis/q/?substancia=25722

Planalto. LEI Nº 6.360 DE 23 DE SETEMBRO DE 1976. Retrieved September 27, 2024, from: https://www.planalto.gov.br/ccivil_03/leis/l6360.htm?TSPD_101_R0=827811d9dba6b3420f0cdafd692d9c14a190000000000000000ae8a3 cbdffff00000000000000000000000000005af1b38d00a8b5ba78#:~:text=Do%20Registro-,Art.,registrado%20no%20Minist% C3%A9rio%20da%20Sa%C3%BAde

São Paulo State Legislative Assembly. (2023). Law No. 17,618, of January 31, 2023. São Paulo, SP. Retrieved from https://www.al.sp.gov.br/repositorio/legislacao/lei/2023/lei-17618-31.01.2023.html

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U.S. Food and Drug Administration (FDA) (2023). FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. FDA. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms