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A evidência mais antiga da planta canábis com um nível elevado de delta-9-tetrahidrocanabinol (THC1), encontrada na região da “Eurásia” devido às suas propriedades psicoativas ou farmacológicas e foi recolhida a partir de uma escavação de uma sepultura com 2700 anos de um xamã.

Fonte: Grof, C. P. L. (2018). Cannabis, from plant to pill. British Journal of Clinical Pharmacology, 84(11), 2463–2467. https://doi.org/10.1111/bcp.13618

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Licenciada em Biologia, e atualmente frequento o mestrado em Microbiologia, na Universidade de Aveiro.

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Licenciado em Bioquímica pela Universidade de Coimbra e a frequentar o mestrado de Bioquímica Alimentar

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Licenciado em Bioquímica pela UA e a frequentar o mestrado de Biologia Aplicada.

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Fotografias ilustrativas da recolha e observações microscópicas da amostra recolhida.

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Fotografias ilustrativas da recolha e observações microscópicas da amostra recolhida.

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A) Fotografia do processo de transferência da amostra, para tratamento numa câmara de fluxo laminar.
(B) Fotografia de fragmento de folha demonstrando os tricomas não glandulares e âmbar.
(C) Fotografia de um único tricoma glandular séssil. São percetíveis 4 das suas 8 células secretoras, à direita.
(D) Fotografia de uma semente de cannabis encontrada.

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Os resultados apresentados apontam, coletivamente, para a conclusão mais provável que é que a povoação da cultura Gushi (China) cultivou canábis para fins farmacêuticos, psicoativos ou religiosos.

Ao examinar as evidências botânicas do local onde foi encontrado, conjuntamente com o grau de preservação, a canábis consistia mostrava-se ser uma amostra processada (“pounded”) cujo tamanho de semente, cor e morfologia, sugerem que foi cultivada, e não meramente colhida como sendo uma planta selvagem.

A quantidade considerável de canábis presente (789 g) sem caules ou ramificações implicaria logicamente uma colheita de várias plantas em vez de uma de uma só planta.

É importante ressaltar que não foram evidentes as partes óbvias das plantas de canábis masculina implicando a sua remoção por intervenção do Homem, dado que estas são farmacologicamente menos psicoativas.

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Desde o início da pandemia da COVID-19 e a divulgação da sequência genômica do vírus SARS-CoV-2, causador da doença, vários pesquisadores trabalham em centros de pesquisa do mundo inteiro em busca de uma vacina que possa ser a arma definitiva na batalha contra a COVID-19.

Assim que os pesquisadores desenvolverem uma vacina que seja realmente efetiva contra o vírus e segura para que possa ser utilizada pela população, uma nova etapa se inicia: encontrar um método que permita a produção rápida e em larga escala a custo baixo. Nesse sentido, pesquisadores de todo o mundo já estão se adiantando no processo e buscando maneiras de produzir a vacina assim que descoberta.

Uma das opções é utilizar plantas como biofábricas em um processo chamado de cultivo molecular ( molecular farming). O cultivo molecular consiste na modificação de genes de plantas com o objetivo que elas produzam proteínas específicas que possam ser usadas como medicamentos ou vacinas.

Cultivo molecular

Inicialmente, desde a descoberta do DNA recombinante nos anos 70, a produção de proteínas de interesse farmacológico e industrial tem sido feita com a utilização de microorganismos em sistemas de fermentação e também por meio da da cultura de células transgênicas em mamíferos. Esses sistemas, porém, possuem suas desvantagens como autenticidade da proteína (sequência correta de aminoácidos e modificações pós-traducionais necessárias), questões de biossegurança e também o custo de produção que pode ser alto.

Uma opção relativamente recente é o uso de sistemas vegetais para produção de proteínas de interesse farmacêutico como reagentes para diagnósticos, vacinas e medicamentos. O custo de produção de proteínas através de biofábricas vegetais representa 10% do custo de produção de um sistema baseado em leveduras, podendo esse custo ser ainda relativamente menor quando comparado à produção através do cultivo de células de mamíferos.

Esse método se baseia na possibilidade de produzir essas proteínas de forma heteróloga* utilizando a maquinaria de produção de proteínas do vegetal. A produção dessas moléculas ocorre pode ocorrer através de suspensões de células em laboratório, , sementes (principalmente de leguminosas e cereais), tubérculos como da batata, folhas (alface e espinafre) e frutas (tomate e banana).

Hoje já existem anticorpos, vacinas e proteínas terapêuticas em fase final de pesquisa e ainda alguns já lançados no mercado (reagentes laboratoriais e medicamentos).

Como é feita a produção de proteínas

Há duas forma de produzir proteínas de interesse a partir de vegetais: transformação estável do material genético nuclear ou do cloroplasto (utilizando agrobacterium** ou o processo conhecido como biobalística), e expressão transiente de genes através da agrobacterium de ou vírus que infectam vegetais.

Transformação estável: É a mais comum. Pode ser utilizada em uma série de espécies vegetais. A síntese da proteína recombinante é contínua durante todo ciclo de vida do vegetal, já que o transgene é incorporado ao material genético da planta e multiplicado durante o processo de divisão celular.

Expressão transiente: Nesse caso o transgene é expresso por um breve período de tempo, não sendo constante durante toda a vida da planta. Geralmente é utilizada na verificação da eficiência (da inserção e da expressão do gene) da construção do gene utilizado na transformação e sua efetividade na produção da proteína de interesse.

Cultivo molecular de antígenos em plantas. Fonte: Singhabahu et al., 2016

Utilização de plasmídeos virais

Recentemente a utilização de material genético de vírus que infectam vegetais em combinação com o DNA que codifica para a proteína de interesse tem gerado bons resultados em relação à produtividade dessas proteínas. Nesse caso o plasmídeo (vetor contendo os materiais genéticos virais e da proteína a ser produzida) utilizado infecta a planta também através da agrobacterium.

O método se baseia no fato de que genes virais tem a característica de possuir uma taxa muito alta de multiplicação e consequentemente alta produção da proteína de interesse. Esses sistemas têm utilizado um vírus chamado Vírus do Mosaico de Tabaco (TMZ - Tobbaco Mosaic Virus) para produção das proteínas de interesse em folhas de tabaco (Nicotiana benthamiana) , tendo obtido sucesso por exemplo, para produção de anticorpos de vírus Influenza.

Biotecnologia vegetal e o COVID-19

Pesquisadores doCentro de Pesquisa em Genômica Agrícola (CRAG - Centre for Research in Agricultural Genomics) em Barcelona estão empenhados em produzir antígenos para SARS-CoV-2 que possam ser utilizados como vacina. María Coca e Juan José López-Moya são especialistas em biotecnologia vegetal e virologia, respectivamente. Juntos, eles já produziram um composto ativo antifúngico utilizando plantas de Nicotiana benthamiana e o plasmídeo viral. Agora, estão empenhados em utilizar a mesma tecnologia para produção de antígenos para o SARS-CoV-2, tanto em tabaco quanto em alface. Segundo López-Moya, uma vez que o sistema tenha sido desenvolvido e validado, poderia ser implementado facilmente para produção do antígeno em larga escala.

A empresa canadense Medicago também diz estar trabalhando em uma vacina produzida a partir de biotecnologia vegetal. Segundo o CEO da empresa Bruce Clark, uma vez que tenham aprovação para produção da vacina, seriam capazes de produzir 10 milhões de doses a cada mês.

Para incentivar que outras iniciativas como as citadas acima possam ser desenvolvidas, pesquisadores da Universidade de Tecnologia de Queensland (Austrália) que trabalham no projeto NEWCOTIANA H2020 financiado pela União Européia estão compartilhando dados da montagem do genoma de Nicotiana benthamiana. O time é liderado pelo Prof. Peter Waterhouse, e segundo ele a obtenção de sequências genômicas de alta qualidade é necessária para entender e otimizar os genes, a quantidade e qualidade de compostos biofarmacéuticos produzidos através do cultivo molecular.

Dessa forma o cultivo molecular em plantas pode ser um grande aliado na produção de vacinas e fármacos de forma segura e com baixo custo. Vale a pena ficar de olho nessa técnica e nas suas aplicações tanto visando o combate ao coronavírus quanto no tratamento de outras doenças. Já tinha ouvido falar do cultivo molecular em plantas, o que acha dessa ferramenta biotecnológica? Conta pra gente, vamos conversar!
* Produção de proteínas por uma célula que naturalmente não fazem (ou seja, expressam) tal proteína. ** A transformação genética via Agrobacterium tumefaciens permite a inserção de cópias do transgene (gene de outra espécie) de interesse no DNA da planta hospedeira.

Texto revisado por Priscila Lopes e Natália Videira

Referências:
COVID-19: HOW PLANT BIOTECHNOLOGY CAN HELP. Disponível em <https://www.cragenomica.es/crag-news/covid-19-how-plant-biotechnology-can-help>. Acesso em: 24 de abril de 2020.
EIBEN, S.; KOCH, C.; ALTINTOPRAK, K.; SOUTHAN, A.; TOVAR, G.; LASCHAT, S.; WEISS, I.M.; WEGE, C. Plant virus-based materials for biomedical applications: Trends and prospects.Adv Drug Deliv Rev. v.145, p. 96-118, 2019.
LEITE, M.L., SAMPAIO, K.B., COSTA, F.F., FRANCO, O.L., DIAS, S.C., CUNHA, N.B.. Molecular farming of antimicrobial peptides: available platforms and strategies for improving protein biosynthesis using modified virus vectors. An. Acad. Bras. Ciênc. v. 91, e20180124, 2019 .
MEDICAGO. https://www.medicago.com/en/. Acesso em: 24 de abril de 2020.
NEWCOTIANA MAKES PLANT GENOME PUBLIC TO HELP FIGHT COVID-19. https://newcotiana.org/newcotiana-makes-plant-genome-public-to-help-fight-covid-19/. Acesso em: 24 de abril de 2020.
PLANT BIO-FACTORIES CONTRIBUTING TO THE COVID-19 FIGHT . https://www.drugtargetreview.com/news/60116/plant-bio-factories-contributing-to-the-covid-19-fight/. Acesso em: 24 de abril de 2020.
SHI, X.; CORDERO, T.; GARRIGUES, S.; MARCOS, J.F.; DARÒS, J.A.; COCA, M. Efficient production of antifungal proteins in plants using a new transient expression vector derived from tobacco mosaic virus. v. 17, p. 1069-1080, 2019.
SINGHABAHU, S.; HEFFERON, K.; MAKHZOUM, A. Plant molecular pharming. In book: Transgenesis and Secondary Metabolism, Springer International Publishing, p.1-26, 2016.
GHAG, S.B.; ADKI, V.S.; GANAPATHI, T.R.; BAPAT, V.A. Heterologous protein production in plant systems. GM Crops & Food. 2016.WIKIPEDIA - AGRICULTURA MOLECULAR. https://es.wikipedia.org/wiki/Agricultura_molecular. Acesso em: 24 de abril de 2020.

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Plantas como biofábricas: o papel da biotecnologia vegetal na luta contra a COVID-19

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Desde o início da pandemia da COVID-19 e a divulgação da sequência genômica do vírus SARS-CoV-2 , causador da doença, vários pesquisadores trabalham em centros de pesquisa do mundo inteiro em busca de uma vacina que possa ser a arma definitiva na batalha contra a COVID-19.

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© Thalia Fernández Bustamante

2020 Shaping the Past Fellow Thalia Fernández Bustamente writes about the impact Covid-19 has had on indigenous communities in Mexico and the challenges they are currently facing. Bustamente delves deeper into how indigenous medicinal practices preserve, elevate, and honor ancestral land, culture, flora, and ways of living. She challenges the reader to critically think about the knowledge indigenous communities possess, knowledge that could aid in healing on a physical and spiritual level.

The world is suffering from the Covid-19 pandemic. This pandemic has had physical, social, economic, and cultural impacts, mostly negative, due to the lockdown and the virtual life we now lead as a result of social distancing and public spaces closing. As a result, there have been consequences for both Mexico's and the world's native communities. We have learned to live isolated from our loved ones, our working places, our educational institutions, and our social coexistence methods, such as taking a stroll in historic downtowns which are a gathering point in every state, municipality, and community.

Dealing with a world health crisis like the one we are experiencing is not pleasant for any country, much less for third world countries in Latin America. In Mexico, the majority of the population is divided into suburban zones such as neighborhoods, rural areas and native towns ruled by customs and traditions. These places keep their culture alive by encouraging traditions like gathering for communal labor and tasks, weekly street markets, cultural events, patron saint festivals, sacred and religious ceremonies, among others. These types of communal events maintain the social fabric and keep the memory of people's ancestors alive. Right now, they cannot be held due to the new way of living and the voluntary lockdown brought on by the pandemic.

The pandemic has impacted not only the culture, but the physical health of people in native villages and towns located in rural and urban areas. This population's high rate of secondary illnesses, such as diabetes, high blood pressure, malnutrition, obesity, etc., make them even more susceptible to infection. Increased vulnerability is even higher in populations that live in extreme poverty because they don't have access to basic services like running water, decent housing, a nutritious & balanced diet, and education, all of which they should have a right too. Moreover, the media doesn't reach these places, making information rather scarce. As a result, many of these communities are unaware of the gravity of the disease we are facing, or, if they do know, they don't have access to medical services that diagnose, care for, and combat Covid-19. Even with access to information and healthcare centers, those who are best equipped to battle Covid-19 are extremely far.

On top of this, there are indigenous communities in resistance who for years have defended and safeguarded their land from huge projects imposed by private companies. These companies have taken advantage of the pandemic to keep dispossessing lands and attacking the physical security of locals, the latter of whom are not only facing conflicts as they defend the land, but also the new pandemic. Companies are leveraging the potential of infection to illegally enter these towns. Given infection cases and recent deaths, organizations, collectives, and towns involved in the resistance have been unable to hold demonstrations, rallies, sit-downs, walks, cultural events, among other events, which are part of their ongoing fight and protest strategies against injustices or human rights violations.

However, it is important to highlight that some communities have organized their own protective actions, in some cases through community organizing to help reduce the movement of people or even closing down entirely. They have distributed the main health recommendations through community radio, social media, apps, newspapers, fanzines, or printed posters. It is worth mentioning that despite this effort, some communities (the most remote) still do not have access to the Internet or other methods of communication.

Despite facing limitations and challenges, many communities, towns, and neighborhoods have opted to reclaim their peoples' memory. They have chosen to deal with the Covid-19 crisis with traditional medicine, which is ancestral wisdom that has been used to alleviate physical, emotional, and spiritual illnesses for many years. These are important therapeutic resources due to their beneficial properties. In short, having access to medicinal plants and using them means saving lives in the indigenous world, all while preserving the history of their ancestors. Although it is hard to imagine, the health of our ancestors was in the hands of the wisest women and men in towns, who were elders, shamans, healers and midwives, and heirs to the elemental knowledges of life. There is no doubt that they knew which plants to look for and use, and the exact amounts needed to create a timely remedy for healing.

Remedies inherited by this land allow us to make the most of plants in a different way. For instance, pomades, ointments, shampoo, soap, dye, baths, meals, ceremonies, infusions and others, made with plants, herbs, roots, flowers and barks, such as chamomile, spearmint, Mexican hawthorn, rue, rosemary, lavender, ixtafiate, dandelion, toad herb, epazote, chaparral, French rose, black nightshade, pulque, maguey juice, mushrooms, ginger, etc. All these elements are at hand for most communities. For the indigenous and non-indigenous neighborhoods in the cities, these plants can be acquired at street markets which are, in Mexico, a source of important information because they offer products from many places, and also work as a gathering point for ancestral knowledge. A frequent example of herbs use is the miraculous Temazcal, a circular structure made of stone, clay or bamboo branches where a steam bath is made using infusions from different medicinal plants placed on hot stones. This has different healing purposes for respiratory, digestive or muscular illnesses, although it is also considered a ritual of connection between body, mind, spirit, and nature. Finally, it is worth mentioning that rituals not only improve the body-mind-spirit balance, but they have also been used and kept for generations as an essential part of time and harvests for indigenous peoples. This is why most communities in Mexico uphold the tradition of visiting sacred sites located in the area, whether it is jungles, forests, mountains, or deserts, but which are undoubtedly a symbol for preserving life, culture, education, language and the land itself.

WHO mentions that:

"traditional medicine is any set of knowledge, skills, and practices based on theories, beliefs and indigenous experiences in the different cultures, whether or not these are explainable, used for maintaining health, as well as prevention, diagnose, improvement or treatment of physical or mental illnesses. They refer to a wide set of practices of healthcare that are part of the country's own tradition and are not integrated into the mainstream sanitary system. The concept of herb medicaments covers herbs, herb material, herb concoctions, and finished herb products that contain parts of plants, or other vegetal materials, or combinations of those elements, as main active parts."

Mexico is a pretty fertile country for traditional remedies, on one hand, because of its cultural and ethnic diversity, and on the other, because it is a large territory with a variety of plants, tastes, colors, aromas, and textures that offer useful substances for healing. In this case, medicinal plants provide a range of healing opportunities. That is why it is very important to break paradigms on their usage, continue to further study them, and to create a large network of indigenous communities who can share their knowledge of herb remedies with each other for use in their own communities. It is important to raise awareness through different media platforms, stressing the fact that using these remedies is not bad - they could become a part of current ways of healing in large cities, both nationally and internationally.

Medicinal plants respond to the memory left by our ancestors, as do the roads travelled to collect them - all these plants grow amidst cracks, lanes, bushes, maguey, grass, and corn parcels. The sacred sites that serve as resting stops and places to pray for health, nature, health, and well-being of peoples can also not be forgotten. This is why it's important to keep the world's indigenous communities safe, listen to their needs, give voice to their demands, respect their beliefs, and maintain a connection with indigenous lands and native people, who are a clear example of resistance before so much inequality, and who share and pass down their ancestral knowledge. To provide a decent life and respect nature is to keep an ancestral root present in our learning, since we, as human beings belonging to different times and spaces, are aware that we are also vulnerable to diseases and pandemics, but that, undoubtedly, to value and use the traditional medicine of indigenous communities could save many lives.

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The Ancestral Memory of Medicinal Plants in Covid-19

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2020 Shaping the Past Fellow Thalia Fernández Bustamente writes about the impact Covid-19 has had on indigenous communities in Mexico and the challenges they are currently facing. Bustamente delves deeper into how indigenous medicinal practices preserve, elevate, and honor ancestral land, culture, flora, and ways of living.

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Many South Africans use traditional medicine. Paballo Thekiso/AFP via Getty Images

South Africa has a long tradition of using plants for medicinal purposes. Some of these, such as Aloe ferox, Sutherlandia frutescens and Kiggelaria africana, have been studied as sources of useful compounds. But most still need to be scientifically validated as treatments for particular diseases.

Medicinal plants are gradually gaining prominence in scientists' search for potential treatment agents for COVID-19. Currently there is no specific antiviral drug to treat this new respiratory disease. Most treatment strategies focus on managing symptoms and supportive therapy such as supplementary oxygen and mechanical ventilation.

My colleagues and I from the Durban University of Technology and the University of KwaZulu-Natal in South Africa are among the researchers looking for potential COVID-19 treatments from plants. We recently completed the first phase of our project, which ultimately seeks to develop a novel SARS-CoV-2 therapeutic.

Our aim in the first phase was to identify bioactive compounds in plants that are indigenous to South Africa which could be effective against SARS-CoV-2, the virus that causes COVID-19. We looked for potential COVID-19 therapeutic agents from a list of 29 bioactive compounds. The species chosen were based on their use for the common cold, flu, other respiratory conditions, antimalarial, antiviral and antioxidant activity.

Our initial findings show that some compounds had the potential to inhibit SARS-CoV-2. We are now in the second phase of our study, which will test the compounds rigorously in the laboratory. This is a starting point in the search for a novel SARS-CoV-2 therapeutic.

From plant extract to therapeutic

In the initial stage of this project we worked with collaborators from the University of KwaZulu-Natal, Bio-computational and drug design laboratory. The team screened potential bioactive compounds isolated from commonly used South African medicinal plants using molecular docking.

Molecular docking is the study of how two or more molecular structures (for example, a drug and an enzyme or protein) fit together. Protein-binding may affect drug activity in one of two ways: either by changing the effective concentration of the drug at its site of action or by changing the rate at which the drug is eliminated, thus affecting the length of time for which effective concentrations are maintained.

We performed molecular docking of the plant compounds against SARS-CoV-2, using biocomputational analysis.

Some of the plant compounds showed potential. These were from Acacia senegal, Sutherlandia frutescens, Hypoxis hemerocallidea, Xysmalobium undulatum and Aspalathus linearis (commonly known as rooibos). They exhibited favourable binding orientations and were identified as potential inhibitors of the SARS-CoV-2 receptor binding domain and SARS-CoV-2 RNA-dependent polymerase. Four compounds exhibited extremely good binding to the virus, meaning that these compounds may prevent the virus from replicating.

These compounds could serve as a starting point for the discovery of a novel SARS-CoV-2 therapeutic.

Next steps

For the next stage we will infect animal cells with the virus. Then we'll administer the compounds (cytotoxicity screening) to see what effect they have. If this in vitro study shows promising results, further analysis will be conducted using an animal model. The effects of the compounds on infected rats will be monitored.

Our end goal is to finally have a successful treatment for this virus. Infections can still occur even when a safe and effective vaccine is available. This is why it's important to ensure effective treatments are also part of the efforts to end COVID-19.

No traditional African medicine has been scientifically validated yet as a treatment for SARS-CoV-2.

Read more: Why more must be done to fight bogus COVID-19 cure claims

We are now in the second phase of our study, which will test the compounds rigorously in the laboratory if funding can be found. This depends on a lot of different factors.

We will be working with collaborators from the University of KwaZulu-Natal's Department of Virology, where the analysis will take place.

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South African researchers are looking at medicinal plants for possible COVID-19 treatments

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South Africa has a long tradition of using plants for medicinal purposes. Some of these, such as Aloe ferox, Sutherlandia frutescens and Kiggelaria africana , have been studied as sources of useful compounds. But most still need to be scientifically validated as treatments for particular diseases.

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Psilocybin Mushrooms & The Path to Higher Consciousness

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These Illegal Drugs Are Important Medicines | The War on Drugs

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Papel da Medicina Tradicional Chinesa no tratamento da lesão provocada por Covid-19

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Papel da Medicina Tradicional Chinesa no tratamento da lesão provocada por Covid-19

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-Inibição das vias pró-inflamatórias;
-Possível intervenção na replicação do vírus.

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Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19)

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The Coronavirus Disease 2019 (COVID-19) has been declared as a global pandemic, but specific medicines and vaccines are still being developed. In Chin...

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STERO Biotechs, headquartered in Israel, provides insight into the use of cannabis and CBD as potential treatment for COVID-19 and other conditions

Thanks to universal access to a well-organised healthcare system and constant scientific advances, Israel has had relatively fewer severe cases and deaths in the COVID-19 pandemic.

For decades, Israel has also been a pioneer in investigating the potential mechanisms of action and uses of cannabis and its derivatives for a wide range of medical conditions. STERO Biotechs, a research and development start-up, is committed to the research and development of novel cannabidiol (CBD)-based treatment solutions which will potentially benefit millions of patients. STERO works to achieve further knowhow in its quest for more effective treatments for COVID-19 patients, among other conditions.

Cannabis and COVID-19: friends or foes?

An array of literature has been written on CBD and cannabis as potential treatments for COVID-19. It is important to understand that, depending on the stage of the disease, cannabinoids could either help or harm a patient; as each phase of the disease is likely to require very different treatments. In the early stages, patients must mount an immune response to combat the virus so their immune system must be at its best. In the later stages, however, if a patient with a severe case of COVID-19 develops a cytokine storm, the immunosuppressive function of cannabinoids might be used to fight off its harmful, often fatal effects. Evaluating the safety and efficacy of isolated cannabinoids or Cannabis in general, at various stages of COVID-19 infection in clinical settings, is key.

STERO Biotechs is supporting a clinical study to evaluate the safety and efficacy of STERO's CBD solution for treating patient cytokine storms in severe stages of COVID-19. STERO has extensive experience working with CBD-based drug development from previous trials performed in over 150 patients with Graft Versus Host Disease (GVHD), Steroid-Dependent Crohn's Disease, Chronic Urticaria, and more; searching for effective ways of reducing or eliminating patients' dependence on steroids, as well as helping patients who are refractory to steroids to respond to them.

Cannabis in the early stages of COVID-19

Under normal circumstances, whenever the immune system senses an infection or inflammation, the body releases cytokines into the bloodstream. Cytokines are - proteins, peptides, or glycoproteins secreted by specific cells of the immune system which mediate and regulate immunity, inflammation, and haematopoiesis - by rushing to the site and communicating to white blood cells which virus or cell to attack. Once the infected or damaged cell is destroyed, the cytokines disperse; and the destroyed cells are carried away as waste.

As cytokines play a crucial role in fighting off infections, reducing them as a preventative measure or in early stages of the infection may be a bad idea. Many authorities caution against using cannabis agents in early stages of infection because cannabis and specific cannabinoids such as CBD and THC suppress immune responses.

Patients with weakened immune systems are at higher risk of getting gravely sick or remaining infectious for a longer period of time than others with COVID-19. There are many reasons a person may be immunocompromised or have a weakened immune system, including a solid organ, blood, or bone marrow transplant; immune deficiencies; and prolonged use of corticosteroids or treatments with other immune weakening medicines. ¹

However, some evidence does indicate that several high-CBD extracts can inhibit viral cell entry and spread by decreasing angiotensin-converting enzyme 2 (ACE2) receptor levels, a receptor expressed in lung tissue and the oral and nasal mucosa that SARS-CoV-2 uses for entry into a human host. ² As this data is from in vitro studies only, it is not conclusive and requires further large-scale validation and clinical studies.

Furthermore, observation in patients being treated with other immunosuppressants or anti-tumour necrosis factor (TNF) alpha biologics for inflammatory bowel disease (IBD) or rheumatoid arthritis, indicates they seem to fare better than the general population, needing less hospitalisation, and not reaching the most severe stages of COVID-19. ³ Trials are still ongoing using various anti-TNF alpha treatments.

Cannabinoids and cytokine storms in patients with severe COVID-19 infection

Various studies have shown that cytokine storms, resulting in acute respiratory distress syndrome (ARDS), are a leading cause of death in severe COVID-19 cases. In some cases where cytokine release is necessary, the immune system overreacts, releasing too many proinflammatory cytokines like interleukins IL-6 and IL-1β, as well as immune cells like neutrophils and monocytes. This hyperinflammation is called a cytokine storm; and can become dangerous to patients' health as the immune system attacks the body's own cells instead of the virus, meaning patients may experience high fever, inflammation, severe fatigue, and nausea. In extreme cases, known as hypercytokinaemia, a cytokine storm can become life-threatening and even cause organ failure.

In these cases, the lungs fail to remove harmful gases like carbon dioxide and are unable to efficiently provide oxygen to the body. This helps the virus multiply rapidly in the lungs, resulting in respiratory conditions such as ARDS.

Endocannabinoids produced in the respiratory system and cannabinoid-induced bronchial dilation suggest a significant therapeutic potential for cannabinoids in the treatment of respiratory diseases, including COVID-19-induced ARDS. Several studies mimicking lung damage caused by ARDS in mice show that CBD improved clinical symptoms, significantly improved the levels of oxygen, and reduced the levels of inflammation-promoting cytokines caused by COVID-19 induced ARDS. ⁴ Detailed examination showed that CBD partially or totally reversed the damage caused to the lungs, such as tissue overgrowth, scarring and swelling. A study showed the reason for this is a significant increase in the levels of apelin, a peptide made by cells of the heart, lung, brain, fat tissue and blood that works in reducing inflammation. In the ARDS model, apelin levels dropped close to zero in the lungs and blood, but when scientists gave the mice CBD, apelin levels increased by 20 times. ⁵

Whole plant cannabis extracts have also been shown to reduce blood coagulation in animal models. ⁶ It is known that many of the negative systemic effects of COVID-19 appear to be related to altered coagulation, so it is possible that cannabis may be useful in managing these sequelae too.

However, despite all the observations above together with less grounded rumours and promises, there remains little clear evidence regarding the effect of cannabis on the course of COVID-19.

Exercising caution

A survey of over 1,500 cannabis users in the Netherlands ⁷ showed that during the lockdown, habitual users increased rather than decreased cannabis consumption regarding both frequency and quantity: 41.3% of all respondents reported they had increased their cannabis use since the lockdown measures and 49.4% used it as often as before. Only 2.8% stopped temporarily. One third of those who were not daily users before the lockdown began to use cannabis daily or close to daily.

In the US, cannabis use increased among seniors between 2015 and 2018. ⁸ This is of concern because the most serious complications and highest mortality rates from COVID-19 infection occur in older people. 9 Weakly or unsupported claims on the internet that cannabis use can prevent COVID-19 may have encouraged its use.

Risk may become heightened for regular cannabis smokers: as COVID-19 predominantly kills people by harming their lungs, it seems logical to think that patients whose lungs are irritated and inflamed have a higher risk of lung damage and complications from COVID-19.

Both the FDA and the WHO advise against smoking cannabis to treat COVID-19

Several CBD producers and vendors claiming their products can be used to mitigate the symptoms of or treat COVID-19 have been issued warnings by the US Food and Drug Administration (FDA), which considers the sale and promotion of products with unsubstantiated claims of treating COVID-19 to be a threat to public health. Dubious products promising to cure, treat, or prevent COVID-19 have not been properly evaluated for safety and effectiveness. The main concern is that people may be given the false perception that they are protected from contracting the virus, in the best case; or in the worst, cause them to delay or avoid appropriate medical treatment altogether, leading to serious and potentially fatal outcomes.

The STERO Biotechs contribution to COVID-19 research

STERO Biotechs will supply and support a clinical trial, covered by its IP for Cannabidiol Treatment of Severe and Critical COVID-19 Pulmonary Infection, at Rabin Medical Center (RMC) in Israel, as part of the global effort to fight COVID-19.

The investigator-initiated clinical study running in cooperation with STERO and Mor Research Applications, the TTO arm of Clalit, commenced with the onset of the 'second wave' rise in the number of COVID-19 patients in Israel. The trial has already received Helsinki Committee approval and plans to include 20 patients as a Proof of Concept (POC), using STERO's CBD-based treatment. It will be conducted by Dr Ilya Kagan from the Intensive Care department at RMC.

The study aims to help severely affected COVID-19 patients with respiratory failure stemming from ARDS. The treatment cycle will be 14 to 28 days with a subsequent follow-up period of the same length. Pending the success of this POC, STERO plans to expand and scale to a Phase 2a multicentre study with 40 additional patients, under FDA clinical trial guidelines and regulations.

Founded in 2017 and headquartered in Israel, STERO Biotechs is a clinical-stage company committed to research and development of novel cannabidiol (CBD)-based treatment solutions that will potentially benefit millions of patients by enhancing the therapeutic effect of steroid treatments; lowering the dosage of steroids needed in such treatments, thus reducing their terrible side effects; and allowing refractory patients to begin responding to the steroid treatments they need, all by using STERO's CBD-based treatment. STERO's patent was issued in the US and covers over 130 indications by name, CBD from any source (botanical or synthetic), any dosage, in any combination and any delivery system. The company currently has two ongoing Phase 2a clinical trials and is planning to commence more clinical trials in 2020-2021 for various indications.

One of STERO's main partners and shareholders is MOR Research Applications, the technology-transfer arm of the Clalit Health Services, a 360° HMO, the largest in Israel and second largest in the world. Clalit owns 14 hospitals and around 2,000 clinics, employs 9,000 physicians who provide care for over five million patients. MOR manages the process of finding new indications and commercialising the ideas and inventions conceived at Clalit, so everybody wins: researchers, industry partners, and the public at large.

The concepts of Talent Biotechs and STERO were conceived by one of these physicians and all resources of this gigantic, well-oiled HMO mechanism are available for the continuation of our research and trial work.

References

1. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html#immunocompromised-state

2. Wang, B et al. Aging (Albany NY); 2020 Nov 22;12(22):22425-22444.

3. Robinson et al. The Lancet, Vol. 2, Issue 11, E653-E655, November 01, 2020

4. Khodadadi, H et al. Cannabis Cannabinoid Res. 2020; 5(3): 197-201

5. Salles, E et al. Journal of Cellular and Molecular Medicine. 15 October, 2020

6. Coetzee, C et al. Phytomedicine 2007 May;14(5):333-7

7. Van Laar, M et al. Front. Psychiatry, 21 December 2020

8. Han, BH et al. JAMA Intern Med. (2020) 180:609-11

9. Onder, G et al. JAMA. (2020) 323:1775-6

This article is from issue 16 of Health Europa. Click here to get your free subscription today

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Cannabis and COVID-19 patients: new insights from Israel

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Thanks to universal access to a well-organised healthcare system and constant scientific advances, Israel has had relatively fewer severe cases and deaths in the COVID-19 pandemic. For decades, Israel has also been a pioneer in investigating the potential mechanisms of action and uses of cannabis and its derivatives for a wide range of medical conditions.

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Would you have ever imagined that psychedelics could represent the face of a new era of medicine? Psychedelics, also known as hallucinogens, are a class of psychoactive drugs that produce changes in one's perception, mood, and cognitive processes (1). Psychedelics can affect all the senses, causing hallucinations and changes in perception of time and emotions (1).

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Tirei Licenciatura em Biologia na Universidade da Madeira, e neste momento frequento o Mestrado em Biologia Aplicada na UA.

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A espécie Lophophora williamsii, pertence à família botânica Cactaceae, e encontra-se no chamado deserto de Chihuahua, uma região geográfica que abrange território mexicano e americano. Consoante os grupos étnicos que o consomem, este cato pode ter diversas designações, porém as mais conhecidas e são a de peiote e botões de mescal (nome comercial).

O primeiro relato de colheita e consumo de peiote surgiu em 1560, através de testemunhos de missionários jesuítas espanhóis, que afirmavam que populações indígenas no México o faziam num contexto religioso usufruindo, também, das suas propriedades medicinais.

Nestes momentos de culto religioso, o curandeiro ingere o peiote e em seguida, comunica com uma entidade espiritual maliciosa, que acredita ser responsável por determinada doença ou até pela morte de um indivíduo, enquanto decorrem uma sequência de alucinações.

Atualmente, o peiote é ingerido por algumas populações nativas do México, como os Tarahumaras ou os Huicholes e pelos membros da, Religião Nativo-Americana e, neste contexto, é tido como sacramento.

Um estudo publicado em 2020, diz que o peiote é utilizado nestas práticas há mais de 7000 anos.

Fontes: Shultes  RE,  Hoffman  A  (1982)  Plantas  de  los  Dioses:  orígenes  del  uso  de  los  alucinógenos.  Fondo de Cultura Económica, México, DF, Mexico.

Mandujano, M. C., García Naranjo, A., Rojas-Aréchiga, M., & Golubov, J. (2020). Conservation Status, Germination, and Establishment of the Divine Cactus, Lophophora williamsii (Lem. Ex Salm-Dyck) J. M. Coult., at Cuatro Ciénegas. Cuatro Ciénegas Basin: An Endangered Hyperdiverse Oasis, 227–240. doi:10.1007/978-3-030-44963-6_14.

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Distribuição geográfica da espécie L. williamsii

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Distribuição geográfica da espécie L. williamsii

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O género Digitalis purpurea são plantas herbáceas pertencentes à família Plantaginaceae. O interesse por esta planta ocorre desde o século XVII, tendo sido encontrado as primeiras referências em meados de 1250 em receitas de monges irlandeses escrito na língua celta. Somente em 1542 são encontrados registos pela primeira vez do nome Digitalis no livro “De Historia Stirpium”, escrito por Leonardo Fuchs. Porém, só em 1727 no livro “Dictionaire ou Traité Universel” encontra-se citado o nome Digitalis purpurea escrito por Nicolas Lemery, que descreve a planta como Digitalis purpurea vulgaris. Apesar destas evidências, o interesse e uso da planta para aplicações medicinais/farmacológicas começou através do estudo realizado por um médico e botânico inglês denominado por William Withering. Até ao estudo realizado por William Withering, as únicas evidências de efeitos causados pela Digitalis seriam de vómitos violentos. Através da experiência de William realizado em 157 pacientes, foi possível evidenciar os efeitos benéficos da planta principalmente sobre o coração. Toda a sua experiência e resultados foram registados na sua monografia
“ An account of the foxglove and some of its medicinal uses: with practical remarques on dropsy and other diseases”.

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Monografia do botânico William Withering

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Na imagem estão representados os chamados botões de mescal - parte superior do cato, depois de serem colhidos e secos, para posterior consumo.

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Só em 1867 é que foi possível obter um dos constituintes da planta, por Nativelle, designado por digitalina, e em 1922 outros 4 componentes: ditoxina, digitonina, digitalium verum e anidrogitalina.
Em Portugal foi em 1553 a primeira vez que foi mencionado a Digitalis purpurea por João Rodrigues Castelo Branco. Nos dias de hoje são utilizados vários componentes ativos da Digitalis purpurea em determinadas terapias.

Fonte: Silva, J. (2012). Contribuição para o estudo molecular e morfológico de espécies do género Digitalis L. Universidade de Lisboa - Facudade de Farmácia.

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Contém digoxina (glicosídeo cardenolídeo) - importante medicamento cardíaco, utilizado em casos de arritmia e insuficiência cardíaca.

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Fonte: https://www.researchgate.net/figure/Cardenolide-biosynthesis-through-progesterone-5b-reductase-P5bR_fig10_267802786

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Tal como referido antes, o peiote ainda hoje é consumido num contexto religioso, no entanto o uso desta planta em atividades ligadas ao turismo psicadélico e ao uso recreacional. Quando os botões de peiote são consumidos - mastigados depois de secos ou numa infusão, o utilizador experiencia momentos de felicidade e hipersensibilidade, primeiro, e depois um período de calma, lentidão dos movimentos musculares e alucinações visuais coloridas.
Ao nível de efeitos imediatos no organismo e da toxicidade associada ao consumo dos botões desta planta, esta é muito baixa, sendo que o “pior” que pode acontecer serão dores de estômago, vómitos ou diarreia.

Fonte: Carstairs, S. D., & Cantrell, F. L. (2010). Peyote and mescaline exposures: a 12-year review of a statewide poison center database. Clinical Toxicology, 48(4), 350–353. doi:10.3109/15563650903586745

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Os cogumelos mágicos podem ter sido usados como uma técnica rápida de indução de transe para ajudar a proteger os xamãs mais velhos dos rigores físicos do método habitual de indução envolvendo muitas horas ou dias de canto.

Também existem evidências do uso de cogumelos mágicos como terapia/ritual entre diferentes sociedades tribais datados com centenas de anos. Um dos exemplos está relacionado com uso dos componentes psicóticos, derivados de cogumelos mágicos principalmente do género Psilocybe sp.,(existem 144 sp. das quais 81 possuem componentes alucinogénios), em rituais religiosos na sociedade Pré Mesoamericana Columbiana,(maias, astecas, índios huasteca totonac, mazatecas e mixtecas), desde 1000-400 A.C a 500-1000D.C. O objetivo do uso destes alucinogénios era de atingir um estado de transe e de abertura da mente, introspeção e de comunicação com os espíritos divinos.

Fonte: Carod-Artal, F. J. (2015). Alucinógenos en las culturas precolombinas mesoamericanas. In Neurologia (Vol. 30, Issue 1, pp. 42–49). https://doi.org/10.1016/j.nrl.2011.07.003
Nyberg, H. (1992). Religious use of hallucinogenic fungi: A comparison between Siberian and Mesoamerican cultures. Karstenia, 32(2), 71–80. https://doi.org/10.29203/ka.1992.294

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Isolado pela primeira vez em 1897, mescalina é o principal composto do peiote que confere os efeitos acima descritos. Como a psilocibina, a mescalina é um agonista para recetores de serotonina, com forte afinidade em específico para o 5HT2A mas pouca potencia por comparação. Foram feitos estudos sobre o seu efeito no tratamento de diferentes tipos de depressão e dependências, especificamente de tabaco e álcool. No entanto, a dose normal para ser humano (entre 200 a 400 mg) não apresenta efeitos terapêuticos significativos em nenhum dos casos.

Kyzar EJ, Nichols CD, Gainetdinov RR, Nichols DE, Kalueff A V. Psychedelic Drugs in Biomedicine. Trends Pharmacol Sci. 2017;38(11):992-1005. doi:10.1016/j.tips.2017.08.003

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Até onde vai o consumo de cogumelos psicadélicos?

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Até onde vai o consumo de cogumelos psicadélicos?

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Alguns estudos apresentam evidências, como por exemplo a descoberta e interpretação de arte rupestre tidas como as mais antigas do mundo, no noroeste de Austrália conhecidas por Gwion Gwion ou pintura Bradshaw,  que sugere o uso de cogumelos mágicos desde  10.000 A.C. Foram encontrados pinturas rupestres representativas de “cabeças de cogumelos” e que por meio de comparação foi observado o mesmo gênero de pinturas rupestres tanto na arte rupestre Bradshaw (tribo extinta) como em Sandawe (existente).

Fonte: Pettigrew, J. (2011). Iconography in Bradshaw rock art: Breaking the circularity. Clinical and Experimental Optometry, 94(5), 403–417. https://doi.org/10.1111/j.1444-0938.2011.00648.x

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Como é a que Covid-19 influenciou o mercado da Cannabis...

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Como é a que Covid-19 influenciou o mercado da Cannabis...

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"Five days after Gov. Steve Sisolak issued his first emergency declaration, the Nevada Health Response COVID-19 Risk Mitigation Initiative announced that licensed cannabis stores and medical dispensaries could remain open, but encouraged delivery business and social distancing. Mr. MacLean remembers lines of cars, five blocks long, waiting for curbside pickup."

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For many Americans, having enough marijuana was as essential as stocking up on toilet paper. And suppliers found a way to get it to them.

Plants ready for harvest at Aether Gardens, a 120,000-square-foot cannabis producer 14 miles from the Las Vegas Strip. Credit... Joe Buglewicz for The New York Times

This article is part of Owning the Future, a series on how small businesses across the country have been affected by the pandemic.
"I expect this will be the first year Nevada does over a billion in cannabis sales," said Nicolas MacLean, chief executive of Aether Gardens, a cannabis producer in Las Vegas. "And it happened on the back of what I think no one expected."

Last March, the Strip went dark in its first total shutdown since the assassination of the Rev. Dr. Martin Luther King Jr. in 1968. In the ensuing weeks, Las Vegas became the layoff epicenter of the United States. With casinos closed, visitor volume dropped to a little over 100,000 in April 2020 from 3.5 million in January 2020. The decrease sent the state's small businesses - including the cannabis sector - into a tailspin.

"That first week, the government didn't differentiate between essential and nonessential businesses," Mr. MacLean said. "Dispensaries went into panic mode, asking if they could send product back to us." (Recreational marijuana is legal in Nevada, though only licensed dispensaries may sell it.) Inside Aether Gardens, a 120,000-square-foot space 14 miles off the Strip, Mr. MacLean and his staff marveled at their latest harvest.

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Freshly cut plants are prepared storage at Aether Gardens. Credit... Joe Buglewicz for The New York Times

"We'd spent the last year perfecting our flower," Mr. MacLean said, "and we got caught in the middle of Covid with the best flower we'd ever had."

At the time, the company was offering the Dosi-Woah, a calming strain in which the indica species is dominant, with buds in a mix of green, gold and bright orange. It also had Zweet Insanity, a strain rich in terpenes, the compounds responsible for the plant's often powerful scent, with big, greasy blooms that provide a relaxing effect. Both varieties also deliver the high levels of the psychoactive compound tetrahydrocannabinol (THC) that hard-partying visitors seek. But with none of those customers in town, Mr. MacLean saw cannabis through a new lens: How could it help with pandemic-related stress and anxiety?

Apparently, quite a bit. Despite inconsistent public health orders from state and local governments about whether cannabis companies would be considered "essential," the industry had a breakout moment during the pandemic. Legal cannabis sales in the United States passed $17.5 billion in 2020, a 46 percent increase over sales in 2019. For many Americans, stocking up on marijuana was as essential as stocking up on toilet paper. And the industry found a way to get it to them.

"We'd spent the last year perfecting our flower," said Nicholas MacLean, Aether Gardens's chief executive, "and we got caught in the middle of Covid with the best flower we'd ever had." Credit... Joe Buglewicz for The New York Times

In Las Vegas, that meant engaging local residents. Five days after Gov. Steve Sisolak issued his first emergency declaration, the Nevada Health Response COVID-19 Risk Mitigation Initiative announced that licensed cannabis stores and medical dispensaries could remain open, but encouraged delivery business and social distancing. Mr. MacLean remembers lines of cars, five blocks long, waiting for curbside pickup. While Nevada businesses had always bet on tourism dollars, Las Vegas's metropolitan population of two million year-round residents suddenly looked like a strong replacement-customer base.

"Locals are very discerning - they want something they aren't going to find on the black market," he said. "Especially when you are stuck at home, you're paying more attention to things like terpene and cannabinoid profiles, on top of THC levels, bud structure and aroma, which is information you get when buying from the legal market. And last year, that played into our hand as a high-quality flower cultivator."

To meet the growing demand, Aether Gardens built a new state-of-the-art greenhouse, which will deliver its first harvest this month. Tourists (and their discreet vape pens) are coming back, but Mr. MacLean doesn't anticipate that local business - or the demand for premium flower - will go away anytime soon.

Oswaldo Graziani Lemoine, the creative director of the Florida-based company Fluent Cannabis Care, saw a similar demand for flower when the pandemic hit. But he knew exactly who was buying: the half a million or so Florida residents who hold medical cannabis cards. (Adult recreational use is not legal in the state.) The question was, how would Fluent manage retail during the pandemic?

"Florida is a place where mask-wearing gets political," Mr. Graziani said, "so even though we were able to keep our 19 locations open, we incentivized online orders and curbside pickup." That included deals like Silver Sundays (10 percent off for ages 55 and older), Student Saturdays (10 percent off with a student ID) and, throughout the week, 20 percent off express pickup (curbside pickup of online orders) for new customers.

"For us, it became less about the in-store experience and more about offering our customers deals and the ease of pickup," Mr. Graziani said. As the company looks to future expansion, he is imagining stores that are exclusively for express pickup: no lobby, no counter, just preorder and drive-through.

"If you don't like roadblocks thrown at you all the time, like a video game, this is not the industry for you," said Meg Sanders, chief executive of the Massachusetts-based Canna Provisions. In March 2020, the hurdles came fast and furious. Though recreational marijuana use is legal there, Massachusetts is the only state to distinguish between medical cannabis distributors and adult-use retailers, which meant that dispensaries like Canna Provisions had 48 hours' notice to shut down.

"To have liquor stores deemed essential and not adult-use cannabis - especially when the law passed in Massachusetts was about regulating cannabis like alcohol - was surprising and unfortunate," Ms. Sanders said. After paying all of her employees for an additional two weeks and coming to terms with the fact that the cannabis businesses were not eligible for Paycheck Protection Program loans, she took a hard look at her business model and began to sketch out a way forward.

"We immediately understood that our way of interacting with our customer would have to change, Ms. Sanders said, describing the focus at the Canna Provisions dispensary in Lee, Mass., as education-focused personalized service. Located in the heart of Berkshire County, where nearly three million visitors come every year for leaf peeping, skiing and picnicking, "our store is very much part of the experience," she added.

In contrast to the traditional deli-counter-style dispensary, Canna Provisions has thrived on interactive, guide-led group shopping. "Our average customer age is 50 or over," Ms. Sanders said. "They have questions, they want to learn, they don't want to feel rushed because there is a line growing behind them." Prepandemic, Canna Provisions had as many as eight guides on the floor at a time, educating groups on topicals, brownies and prerolled joints. But during the pandemic, that atmosphere of weed-focused learning vanished.

"Picture that transaction in a parking lot, with two people wearing masks, six feet apart, and it's just not the same," Ms. Sanders said.

Canna Provisions faced another obstacle when it eventually reopened, with limited curbside pickup, two months after the shutdown. "Our county is an internet desert, so we had to help people that didn't have access or didn't have the computer skills they might need to preorder online., Ms. Sanders said. Facing this reality, she transferred her operations to telephone orders to preserve the human and educational touch that customers had grown comfortable with.

Canna Provisions provides a guided experience, putting customers in touch with bud tenders. Credit... Jessica Hill for The New York Times

When clients call Canna Provisions, the first voice they hear is that of an adept bud tender - sometimes Ms. Sanders herself - who guides them through the shopping experience. From suggesting strains - like the locally grown Stardawg (Corey Cuts) Smash Hits, a relaxing and uplifting hybrid with "a tendency to turn philosophical," as the company's website puts it - to processing the order, each phone guide provides the same dedicated attention that clients would experience at the shop.

"And it's working," Ms. Sanders said. "In our Lee store, preorders have become almost 100 percent of our business, so we bought more handsets and hired more people to answer the phones, and our revenue is up."

When Covid restrictions for retail operations eased last summer, Canna Provisions opened its second shop, inside a 150-year-old brick paper mill in Holyoke, Mass. At the new 4,000-square-foot location, Ms. Sanders and her team can once again offer their guide-led customer-service experience. She described the way cannabis tourists explore the space and take in all the curious design elements: antique rubber stamps, reclaimed metal signs and the figurine of a T. rex smoking a joint.

"We set out to make a destination," she said. "And we nailed it."

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Why the Pandemic Was a Breakout Moment for the Cannabis Industry

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For many Americans, having enough marijuana was as essential as stocking up on toilet paper. And suppliers found a way to get it to them. This article is part of Owning the Future , a series on how small businesses across the country have been affected by the pandemic.

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Pintura rupestre: a) Tribo Bradshaw; b) Tribo Sandawe

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Desde os tempos antigos, que as pessoas procuravam na natureza antídotos como cura para as suas doenças. A descoberta do poder curativo de determinadas plantas era realizada de uma forma intuitiva, baseado em experiências e por tentativas a erro. Estudos arqueológicos provaram que as propriedades curativas das plantas eram conhecidas pelos povos em tempo pré-histórico. Existem registos antigos escritos do uso de plantas medicinais desde á cerca de 5000 anos como o encontrado numa laje de argila suméria de Nagpur, no livro chinês titulado "Pen T'Sao", escrito pelo Imperador Shen Nung por volta de 2500 a.C., ou até mesmo na Bíblia onde é possível encontrar referências a rituais onde eram utilizadas plantas aromáticas com propriedades curativas.

Fonte: Petrovska, B. B. (2012). Historical review of medicinal plants’ usage. Pharmacognosy Reviews, 6(11), 1–5. https://doi.org/10.4103/0973-7847.95849

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Can LSD cure our pandemic anxiety? MindMed is spending big to find out

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MindMed is one of several companies experimenting with psychedelics to treat anxiety and addiction.

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Fonte: https://www.discoverlife.org/20/q?search=Digitalis+purpurea

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O estudo destas espécies de cogumelos tem o seu início em 1957 e não demorou mais do que um ano até o composto ativo ser isolado e identificado. A Psilocibina é então a molécula responsável pelos efeitos psicoativos dos cogumelos mágicos. Quando entra no organismo é rapidamente desfosforilada e convertida em psilocina, possibilitando a sua absorção no intestino. Ambos os compostos são agonistas para alguns tipos de recetores de dopamina e vários de serotonina, com uma maior afinidade para os 5HT1A e 5HT2A. Estas interações tornam possível a comunicação entre partes do cérebro que normalmente não comunicam conferindo, assim, efeitos alucinogénicos.

Tylš F, Páleníček T, Horáček J. Psilocybin - Summary of knowledge and new perspectives. Eur Neuropsychopharmacol. 2014;24(3):342-356. doi:10.1016/j.euroneuro.2013.12.006

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Psilocibina

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Laje de argila suméria de Nagpur

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Livro chinês "Pen T'Sao"

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Várias culturas ancestrais contribuíram para o desenvolvimento e conhecimentos das ciências farmacêuticas e fitofarmacêuticas como por exemplo a Antiga Grécia, a China com a medicina tradicional chinesa e a Índia com a terapia Ayurveda entre muitas outras.
Este conhecimento adquirido entre as diferentes sociedades ancestrais foi transferido de geração em geração possibilitando o melhoramento de propriedades medicinais assim como a descoberta de novas até os dias de hoje.

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The few references to drug taking in the ancient world that do exist are few and far between. Where they do appear, drugs are mentioned in passing, and focus on medicinal and religious aspects, passing hastily over any recreational use. Yet there was an international drug trade as far back as 1000 BC, and archaeology has combined with science to clarify a picture that seems to have been carefully obscured by ancient writers and their later translators.

There were more than a dozen ways of altering reality in the ancient world of the Mediterranean, but two drugs dominated - opium and hemp. Careful investigation over the past two decades has begun to reveal patterns in the use of these drugs, previously unsuspected even by 20th-century Classical historians.

Opium's emergence

One of the first clues that the ancients considered the poppy to be more than just a pretty plant comes from its prevalent use as a motif on statues and engravings. Archaeologists have found that, as early as 1600 BC, little flasks were being made in the shape of poppy 'capsules' - the bulging ball under the flower's petals that yields opium. The shape of these artificial capsules allowed for a reasonable guess as to what was contained within, but until recently it was impossible to be certain.

In 2018, the journal Science reported that new techniques for analysing the residues in excavated capsules had revealed that the plant material within contained not just opium, but sometimes other psychoactive substances. These jars and capsules have been found throughout the Levant, Egypt and the Middle East. Their uniformity suggests that they were part of an organised system of manufacture and distribution.

Yet even earlier, opium was grown in Mesopotamia. Some researchers have no doubt that the Assyrians were aware of the plant's properties. Indeed, the Assyrian name of the poppy can be read (depending how one interprets the cuneiform tablets which mention it) as Hul Gil, meaning 'Happy Plant'.

Jugs containing opium residue have also been found in Egyptian tombs, which is unsurprising given that the poppy was extensively cultivated in Egypt. In the Classical era, the extract of the plant was known as 'Opium Thebiacum' after the city of Waset, which the Greeks knew as Thebes. Another version was named Opium Cyrenaicum, a slightly different version of the plant, grown to the west in Libya.

Sleep eternal

There is a highly suggestive passage in Homer's The Odyssey, in which Helen of Troy dopes wine with a drug "that took away painful memories and the bite of pain and anger. Those who took this drug dissolved in wine could not shed a tear even at the death of a parent. Indeed not even if his brother or son were put to the sword before his eyes". This drug, said Homer, had been given to Helen by Polydamna, wife of Thon - a woman of Egypt.

The name Thon is significant, because the Roman doctor Galen reports that the Egyptians believed that the use of opium was taught to mankind by the similarly named god Thoth. The Greek writer Dioscorides describes his harvesting technique: "Those who make opium must wait until the dew has dried away to cut lightly with a knife around the top of the plant. They take care not to cut the inside. On the outside of the capsule, cut straight down. As fluid comes out wipe it with a finger onto a spoon. Returning later one can harvest more of the residue after it has thickened, and yet more the following day.

Dioscorides also warns against overdosing. "It kills," he says bluntly. In fact, many Romans purchased opium for just that reason. Suicide was no sin in the Roman world, and many people suffering from old age and disease chose to instead float from life on a gentle wave of opium. It is unlikely that the Greek divinities Hypnos (the god of sleep) and "anatos (his twin brother, the god of death) are both depicted with wreaths or bouquets of poppies by coincidence. Opium was a common aid to sleep while, writes Greek philosopher Theophrastus, "from the juice of the poppy and hemlock comes easy and painless death".

The Romans used an opium-based drink called 'cretic wine' as a sleep aid, and also 'mekonion' from poppy leaves - which was less potent. The opium could be purchased as small tablets in specialist stalls in most marketplaces. In the city of Rome itself, Galen recommends a retailer just off the Via Sacra near the Forum.

In Capua, drug sellers occupied a notorious area called the Seplasia, after which 'Seplasia' became a general name for mind-altering drugs, perfumes and unguents. Cicero makes a tongue-in-cheek reference to this, remarking of two dignitaries: "They did not display the moderation usually found in our consuls ... their gait and behaviour were worthy of Seplasia."

More than old rope

Hemp has a longer history than opium, brought to Europe before records began. It came from Central Asia along with the mysterious Yamnaya people, and the plant has been in northern and central Europe for over 5,000 years. Doubtless it was appreciated for its uses in making rope and fabric, but braziers have been found containing charred cannabis, which shows that the less practical aspects of the plant were also explored. It is known that the Chinese were cultivating cannabis significantly stronger than the wild plant at least 2,500 years ago, and both the product and knowledge of how to make it would have travelled along the Silk Road.

In the Middle Eastern city of Ebla, in what is now Syria, archaeologists found what appears to have been a large kitchen not far from the city palace. There were eight hearths used for preparations, and pots capable of containing up to 70 litres of finished product.

There were no traces of food remnants, as is usually the case in ancient kitchens; analysis of the containers found there leaves little doubt that this room was used solely for the preparation of psychotropic pharmaceuticals. In other words, the ancient world had largescale drug factories 3,000 years ago.

The Greek physician Dioscorides was also familiar with cannabis and reported that extensive use tended to sabotage the user's sex life, to the point that he recommends using the drug to reduce sexual desire in persons or situations where such impulses might be considered inappropriate. Another Classical author interested in better living through chemistry was Roman philosopher Pliny the Elder. His Natural History lists the properties of many plants, among them "laughing weed", which he says is "intoxifying" when added to wine. Galen describes how hemp was used in social gatherings as an aid to "joy and laughter". Half a millennium beforehand, Greek historian Herodotus reported something similar.

It appears the Scythian people living near the Black Sea combined business with pleasure. Herodotus - who was an extraordinarily good anthropologist, as well as the world's first historian - remarks that they made garments of hemp so fine that it was impossible to distinguish them from linen.

"The Scythians thereafter take seeds from the hemp and throw them on red-hot stones, where [they smoulder] and give off fumes," writes Herodotus. "They cover this with mats and crawl under while fumes emerge so densely that no Greek steam bath could produce more. The Scythians howl with joy at their vapour bath."

Blind to the truth?

This passage is rather typical of mentions of drug usage in the ancient world. Was Herodotus really so naive that he didn't recognise the drug's influence? Or was there a taboo about discussing the subject - either in the Classical world or in the monasteries where the ancient texts were copied and preserved?

It seems strange that while archaeological finds suggest recreational drug use was far from uncommon in antiquity, all references to it are at least as oblique as that of Herodotus, and vanishingly rare in even such cases.

Even medicinal uses of cannabis are hard to find in ancient texts - but are being found now that archaeologists know what to look for. For example, a fourth-century AD Roman tomb of a 14-year-old girl who had died in childbirth was found near the city of Beit Shemesh (near Jerusalem) in the 1990s. A substance found in the skeleton's abdominal area was assumed to be incense, until scientific analysis revealed it to be tetralydrocannabinol - a component of cannabis. It seems likely that the drug was used to ease the girl's travails, and eventually to aid her passing from life itself.

When it comes to drugs in ancient world, we need to read between the lines - as is the case with so much of history.
Philip Matyszak has a doctorate in Roman history from St John's College, Oxford and is the author of many books on classical civilisation. This article first appeared in the August 2019 issue of BBC History Revealed

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Happy plants and laughing weeds: how people of the ancient world used - and abused - drugs

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The few references to drug taking in the ancient world that do exist are few and far between. Where they do appear, drugs are mentioned in passing, and focus on medicinal and religious aspects, passing hastily over any recreational use.

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Long before pure chemicals were manufactured in labs, people used plants for medicine. There are over a hundred active ingredients derived from plants for use as drugs and medicines. This is by no means a comprehensive list of all of the plants, names of chemicals, or uses for those chemicals, but it should serve as a useful starting point for further research.

For your convenience, the common name of a plant is noted next to its scientific name.

Common names are imprecise and often assigned to completely different plants, so use the scientific name when looking for additional information concerning a plant.

List of Drugs from Plants

Reference: Much of the material contained in this table is from Leslie Taylor's Plant Based Drugs and Medicines from RainTree Nutrition (2000).

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This List of Plant-Derived Medicines May Surprise You

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Long before pure chemicals were manufactured in labs, people used plants for medicine. There are over a hundred active ingredients derived from plants for use as drugs and medicines. This is by no means a comprehensive list of all of the plants, names of chemicals, or uses for those chemicals, but it should serve as a useful starting point for further research.

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Psilocina

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"This is exciting because not only can we potentially improve overall survival of medulloblastoma patients with digoxin, but the results also suggest that we could potentially reduce the dose of radiation necessary when combined with digoxin, and thereby minimize long-term side effects of radiation among the survivors".

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Digitalis lanata, the woolly foxglove, is the source of dioxin, a medication long used to treat heart conditions that has now been found to have potential for treating medulloblastoma, the most common malignant brain tumor in children. Credit: Michael Wolf via Wikimedia Commons

Some drugs for heart disease might also work against brain cancer, according to an analysis by researchers from the Jackson Laboratory (JAX), Connecticut Children's Medical Center (CCMC), and UConn Health. The researchers used a new approach to identify five heart medicines that might also be effective at fighting the most common type of childhood brain cancer, they report in the Oct. 24 edition of Science Translational Medicine.

Medulloblastoma is the most common malignant brain tumor in children, accounting for 20 to 25 percent of pediatric brain tumors. Current treatments have significantly increased the survival rate, but many children face difficult side effects from the treatment that impact their brains, hormones, and fertility for the rest of their lives. There are also a handful of patients who either don't respond to available treatment options, or suffer and die from relapses.

Better treatments for medulloblastoma, ideally ones with fewer side effects, are sorely needed. But developing new cancer drugs is a time-consuming process, relying on multiple years of clinical research, followed by a minimum 10-month Federal Drug Administration (FDA) approval process. Now, thanks to a new computational approach, the FDA's extensive approval process could become a benefit for drug discovery instead of just a hurdle.

The research team already knew that data about drugs gathered during the first FDA approval process could be re-analyzed to find crossover between the diseases that a drug is likely to treat. This process is called systematic drug repositioning, and it uses computational modeling methods to compare an approved drug's gene expression profiles - that is, what genes it works with or against - to the genes active in patients with a disease.

But medulloblastoma tumors are complex and often very different from patient to patient, and even internally in a single patient. UConn Health professor Ching Lau, thought systematic drug repositioning could work to find better drugs for medulloblastoma, but suspected the technique could be improved. Lau, who is jointly appointed as a professor at JAX, UConn Health, and Connecticut Children's Medical Center, heads the division of pediatric hematology-oncology at UConn Health and is the medical director of hematology-oncology at Connecticut Children's.

Pediatric oncologist Ching Lau is co-author on a study that found new uses for the heart medication digoxin in the fight against the malignant brain tumor medulloblastoma. Credit: Tiffany Laufer for JAX

Lau worked with a team of researchers from those institutions, as well as Houston Methodist Research Institute, to devise a new systematic drug repositioning method that could work against something as complicated as medulloblastoma.

Their new method has identified eight drugs as possible medulloblastoma-fighting agents, including three already used as chemotherapy against other cancers and five previously used to treat heart failure.

The researchers also showed that one of the heart drugs, digoxin, helped mice with medulloblastomas live longer. The mice survived even longer when digoxin was combined with radiation.

"This is exciting because not only can we potentially improve overall survival of medulloblastoma patients with digoxin, but the results also suggest that we could potentially reduce the dose of radiation necessary when combined with digoxin, and thereby minimize long-term side effects of radiation among the survivors," says Lau. "Because digoxin has been used for so many years to treat heart failure, its potential side effects are well known."

In other words, the potential of digoxin as a medulloblastoma therapeutic looks very hopeful for pediatric cancer patients.

More information: Lei Huang et al. Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma, Science Translational Medicine (2018). DOI: 10.1126/scitranslmed.aat0150

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Old drug, new hope for pediatric brain cancer

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Some drugs for heart disease might also work against brain cancer, according to an analysis by researchers from the Jackson Laboratory (JAX), Connecticut Children's Medical Center (CCMC), and UConn Health. The researchers used a new approach to identify five heart medicines that might also be effective at fighting the most common type of childhood brain cancer, they report in the Oct.

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The science of psilocybin and its use to relieve suffering

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O fitocanabinoide que tem dado que falar ultimamente, conhecido por canabidiol (CBD) presente nas diversas espécies de canabis, representa em média 40% do extrato da planta.

Foi descoberto e identificado em 1940 e recentemente foi alvo de um crescimento exponencial dos seus estudos graças aos seus efeitos no controlo da dor como também de doenças do sistema nervoso, nomeadamente nos diversos síndromes de ansiedade, distúrbios de movimento e problemas cognitivos.
Pensa-se que estes efeitos sejam devido à sua forte afinidade e: atividade antagonista num recetor de proteína G conhecido por GPR55, grande culpado em doenças como a epilepsia; atividade de agonista parcial nos recetores de serotonina 5HT1A que está ligada à diminuição da ansiedade. No entanto o CBD também mostra alguma afinidade para recetores CB₁ e CB₂, GPR3, GPR6 e GPR12, e opióides µ e δ, o que nos leva a acreditar que ainda há muito efeito por descobrir e são necessários mais estudos para este composto se tornar viável como medicamento.

Fonte: Black N, Stockings E, Campbell G, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. The Lancet Psychiatry. 2019;6(12):995-1010. doi:10.1016/S2215-0366(19)30401-8

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Tetra-hidrocanabinol (THC) é um dos parentes chegados do CBD de entre 113 canabinoides já identificados nas várias espécies de canábis.
Foi identificado em 1940 e sintetizado pela primeira vez em 1964.
É o composto que confere os efeitos psicoativos à planta graças à sua forte afinidade como agonista nos recetores endocanabinoides (CB₁ e CB₂) que existem nos neurónios do córtex cerebral, cerebelo, gânglios basais e por todo o sistema imunitário. No entanto tem um grande potencial como analgésico sendo já usado desde 2010 como medicamento alternativo para o alívio de dores neuropáticas em pacientes com esclerose múltipla.

Fonte: Pertwee RG. The diverse CB 1 and CB 2 receptor pharmacology of three plant cannabinoids: Δ 9-tetrahydrocannabinol, cannabidiol and Δ 9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215. doi:10.1038/sj.bjp.0707442

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HIS job was to look after the sickest of the sick. But 'Satan's Son' betrayed their trust in the most horrific way imaginable - killing those he was meant to protect.

HIS job was to look after the sickest of the sick. People recovering from horrific burns and life-threatening illnesses. But 'Satan's Son' betrayed their trust in the greatest way imaginable murdering dozens of patients. Emily Webb tells his story in a new book.

LOVE was what Charles Cullen, a nurse in New Jersey, USA, believed could save him from the death wish that had been his companion since he was a child.

At just nine years of age, Cullen had made his ﬁrst suicide attempt by drinking a mixture from a home chemistry set. The attempts to end his life would continue for years until he found another way to channel the self-disgust, low self-esteem and depression that had plagued him for most of his life. In fact, Cullen's mental torment and victim mentality belied a rat cunning that saw him prey on some of the most helpless, sick and trusting patients whose families believed they were safe and would be nursed with care and compassion.

Little did they know that their loved ones were in grave danger at the hands of Nurse Cullen, who had a compulsion to kill. Cullen was able to hide away by working graveyard shifts in intensive care units (ICUs). The unsociable hours and inability for patients to communicate with him meant that Cullen could murder easily. There was no one to watch him and there was effortless access to his weapon of choice - prescription drugs.

Cullen is serving multiple life sentences at Trenton State Prison, New Jersey, for the murders and attempted murders of 29 patients - he also pleaded guilty to seven murders and three attempted murders while he was working in Pennsylvania. After he was arrested in 2003, Cullen told investigators that he estimated he had killed between 30 and 40 patients during his 16-year career at 10 healthcare facilities. These are the crimes that he confessed to but investigators believe there were many, many more victims, possibly hundreds.

Cullen tried desperately to hide his dark desires by trying to squeeze himself into a so-called normal life that he had craved since childhood. Divorced with two daughters, Cullen was living with a nurse who was pregnant with his third child at the time of his arrest. This was his attempt to ﬁnd the love he had always felt was missing from his life. He told investigators, during a marathon seven-hour interview, that he believed love could halt the sickness in his mind that made him kill.

But Cullen was always a loner and his life was not a success. Neighbours who knew Cullen as a child and young man, described him as socially inept and strange.

Charles Edmund Cullen was born on 22 February 1960 in West Orange, New Jersey, the last of eight children. His family were working class and strong Catholics. Florence Cullen kept the home, as most women did those days, and Edmond Cullen drove buses to pay the bills and feed his brood. Little did the couple know but their little Charlie would grow up to bring shame and shock to the 'Garden State'.

New Jersey (NJ) is famous for musicians Bon Jovi, Frank Sinatra and Bruce Springsteen, among others, but also has a disturbing crime history. Mass murderer John List annihilated his family - mother, wife and three children - in 1971 in their Westﬁeld, NJ, home and then disappeared for 18 years. He was arrested in Virginia in 1989, after a tip to television show America's

Most Wanted when it revisited the crime and revealed a life-like, age-progressed bust of what List may have looked like.

The state is also home to the ﬁrst documented 'lone gunman' killing spree in modern American history. In 1949, Howard Unruh, a 28-year-old war veteran, gunned down random strangers in a street in the town of Camden and killed 13 people, including three children. Unruh died in 2009 at age 88, having spent 60 years in a psychiatric institution.

Tragedy struck the Cullen family when Charles was just seven months old. His father, who was in his late 50s at the time of his youngest son's birth, died and left his wife to struggle alone, raising her children on a pension.

Growing up, little Charles was not popular and was the target of bullies. He was a weedy, pale kid and one that teachers and fellow students would have found hard to remember, had it not been for the fact that he grew up to be one of America's most proliﬁc murderers. He was intelligent but odd and this was what attracted the attention of the other children who would target Cullen's weaknesses and inability to connect with his peers and tease him.

Such was his unhappiness with life that Cullen made his ﬁrst attempt at suicide by drinking a concoction made from a chemistry set. It did not give him the escape he craved so he plunged deeper into a fantasy life and a nihilistic view of the world. He had few friends at Our Lady of Lourdes Grammar School and later, West Orange High School. Further fuelling his dim view of the world was a fascination with the literary works of Fyodor Dostoevsky, the Russian writer famous for Crime and Punishment where the lead character, plagued by mental anguish, plots a murder. The protagonist justiﬁes his action by his belief that the murder of a morally bankrupt pawnbroker was for a higher purpose and would make the world a better place. Dostoevsky

published his famous book in 1866 after years of prison and exile in Siberia.

Cullen would later try to justify his crimes by telling investigators that he was showing mercy to his victims and ending a 'high pain situation'. New Jersey newspaper The Star-Ledger exclusively obtained Cullen's 12 December 2003 confession, in which he portrayed himself as a merciful and compassionate nurse and existed under the illusion that his crimes were a community service. However, Cullen also told police during his confession, as reported by The Star-Ledger exactly one year after his arrest, that he wished he had died the ﬁrst time he attempted suicide as a child. 'You know, maybe if I was nine years old and would have had

to die that day, all these lives, including my family, wouldn't be affected in this way,' Cullen told Somerset County Detective Sergeant Timothy Braun.

Another - perhaps the most - signiﬁcant event of Cullen's young life was the death of his mother when he was 17. Mrs Cullen was killed in a car accident in 1978 and Cullen was said to be devastated. In his senior year of high school, Cullen, despite his reasonable intelligence, was not able to complete his schooling and he dropped out and joined the navy at 18 years of age.

Trained as a ballistic missiles technician from 1978 to 1979, Cullen received his ﬁrst post aboard the nuclear submarine USS Woodrow Wilson. According to the Navy Cyberspace website, which provides information on all things to do with the United States Navy, missiles technicians are 'a vital element in the maintenance of strategic deterrence'. So Cullen had an extremely important job to do, one that you could be forgiven for thinking would give the troubled young man a sense of direction and purpose in life.

However, just like in school, Petty Ofﬁcer Third Class Charles Cullen did not ﬁt in with his navy colleagues who considered the pale, strange teenager a misﬁt. Cullen was the target of relentless bullying during his time on the nuclear submarine and did not last long on his ﬁrst assignment. A disturbing incident, which was reported to superiors by Cullen's shipmates, was when the then-20-year-old was discovered in a stolen hospital gown, gloves and mask, sitting at the missiles control panel of the submarine.

In the 2004 New York Times article 'Death on the Night Shift', the authors tracked down men who had served with Cullen on the Wilson and they reminisced about the very strange behaviour of their now-notorious colleague. Petty Ofﬁcer First Class Michael L Leinen, who discovered Cullen in the strange outﬁt, said while he did discipline Cullen, the reasons for his medical garb was never explained, though it seemed to hint at his healthcare aspirations.

A transfer from the Wilson saw Cullen on a less stressful assignment on the USS Canopus, a supply ship, but this did not help his depression or suicidal tendencies. Cullen made more suicide attempts between 1981 and 1984 and it was this unstable behaviour that led to his discharge from the navy, after serving six years. Interestingly the Wilson submarine was decommissioned and struck from the Naval Register on 1 September 1994. By this stage, Cullen, now a nurse, had already killed at least three patients.

Just a few months after his navy discharge, Cullen enrolled at the Mountainside Hospital School of Nursing in Montclair, New Jersey. The nursing school was founded in 1892 and its website shows photos of bright, young, shiny nursing students. Trying to imagine the sickly, slight Cullen as once being a student there is a difﬁcult task. The alumni page reminds graduates to 'save the date' for a Mountainside Hospital Alumni Association luncheon, a gathering the school's most notorious student deﬁnitely won't be attending.

Cullen, now 27, completed the three-year course in May 1987 but just a few months before his graduation, his brother James died from a drug overdose. In spite of this traumatic event, that year had more hopeful signs for Cullen that any other time of his life. Not only did he graduate but he also married a computer programmer named Adrienne Taub, in July 1987.

Any hope that marriage and the arrival of two daughters would help Cullen out of his depression and maladjustment was short- lived. The marriage was not a success. Cullen had been steadily employed at Saint Barnabas Medical Center in Livingston, NJ, from his graduation until January 1992 when he was ﬁred. Cullen was working in the burns unit of the hospital, where the patients required a very high level of care. It was revealed at his trial that the reasons for his termination were for allegedly tampering with bags of intravenous ﬂuid. The hospital conducted their own internal investigation but police were not contacted at the time.

The couple struggled along until January 1993, when Ms Taub ﬁled for divorce. Cullen admitted to investigators when he was confessing to his crimes that his depression was at its worst that year. Their daughters were aged four and one.

The year of 1993 was a catalyst year for Cullen. Not only was he served with the divorce papers but his behaviour had become increasingly strange, according to statements his ex-wife made to the judge presiding over the proceedings. The truth was that Ms Taub ﬁled for divorce on the grounds of 'extreme cruelty'.

The exact nature of Cullen's behaviour towards his wife was revealed to the public after the Allentown, NJ, newspaper the Morning Call, applied for and was granted access to a domestic violence ﬁle on him. Many of the incidents were also mentioned in the couple's divorce ﬁle, which had already been released to the press. The New Jersey Supreme Court noted in its 2004 decision that 'because Mr Cullen is a serial killer there is a legitimate right of the Morning Call and others to have access to the bulk of this ﬁle. The reality is there is legitimate public interest ...'

Adrienne Taub said in her divorce papers that her husband slept on the living-room couch for three years, was a recluse and never took her out. She also detailed disturbing instances of animal cruelty by Cullen where he would torment the family's Yorkshire terriers to the extent that she and her daughters would be awoken by the pets' terriﬁed yelps. The New York Daily News reported that a former neighbour in Phillipsburg said Cullen would often leave his dog tied up outside for hours at a time in extreme weather conditions and that the Society for the Prevention of Cruelty to Animals ﬁnally rescued the animal. Cullen gets a mention in the People for the Ethical Treatment of Animals' (PETA) report Animal Abuse & Human Abuse: Partners in Crime, which details research that acts of cruelty to animal are symptomatic of a deep mental disturbance in people and that those like Cullen (and many other serial killers) who commit acts of cruelty to animals 'don't stop there'.

Combined with his failed relationship, Cullen was also drinking heavily, as described by his ex-wife in her statements to the court. He also discontinued the medication he was taking for his depression.

The divorce proceedings, his state of mind and his inability to see his children sent Cullen on a rapid descent. Ms Taub ﬁled at least two domestic violence complaints against her estranged husband in 1993 and also a restraining order. The ﬁrst complaint was in January and she claimed that her husband's state of mind and access to medications in his role as a nurse could put her and her daughters at risk. After each domestic violence complaint that Ms Taub ﬁled, Cullen attempted suicide.

Just over a month after his ﬁrst attempt in 1993 to die at his own hand, Cullen took the life of a woman who was initially believed to be his ﬁrst victim, 90-year-old Lucy Mugavero, at the Warren Hospital in Phillipsburg. Mrs Mugavero was killed with

an overdose of the heart drug digoxin, which became Cullen's murder weapon of choice. Digoxin is used to treat the symptoms of congestive heart failure such as shortness of breath and rapid heartbeat. According to the Australian Prescriber website, particular caution is needed when using the drug for elderly patients who often require lower maintenance doses. So for Cullen, the drug provided a quick and easy method of murder in the mostly elderly victims that he killed.

For the Mugavero family, the reason for their loved one's death only became apparent in 2004. The family had never suspected her death was unnatural until the prosecutor's ofﬁce contacted them for a photograph of Lucy Mugavero to show to Cullen. 'I had closure, but this opens everything back up. It makes it seem as though she died yesterday,' Philip Mugavero, Lucy's grandson told the New York Times in 2004.

It turned out that Mrs Mugavero wasn't actually the first person Cullen killed. The ﬁrst victim he admitted to murdering (and only Cullen knows how many people he killed) was in 1988. In 2004, as he was facing court in New Jersey for murdering 24 of his former patients and attempting to kill ﬁve others, Cullen also confessed to the 1988 murder of retired New Jersey municipal judge John Yengo Sr, 72, with a fatal dose of lidocaine, a local anaesthetic. Mr Yengo had been admitted to the burns unit of Saint Barnabas Medical Center for severe sunburn in the days before his death.

Events escalated for Cullen after he killed Lucy Mugavero. A few weeks after he administered a fatal injection to her, Cullen was arrested for stalking Michelle Tomlinson, a nurse he worked with at Warren Hospital - specifically, for breaking into her home while she and her son slept. The harassment began after Cullen took Ms Tomlinson out to dinner. The New York Daily News reported that as well as breaking into her home, Cullen proposed to her at work and bombarded her with phone calls. Again, Cullen attempted suicide a few days after his arrest. He pleaded guilty to trespass.

The next years of Cullen's life were marked by more job changes and murders. Everywhere Cullen worked, there was a cloud of suspicion. He left Warren Hospital in December 1993 and it was under suspicion of murder. Cullen had killed 91-year-old Helen Dean, who was recovering from breast cancer surgery, in the September of that year. He administered a lethal dose of digoxin to Mrs Dean as she was about to be discharged from hospital. In fact, Cullen entered her room, asked Mrs Dean's son Larry to leave and then gave her the injection. Cullen was not even assigned to Mrs Dean's room and after he left, Mrs Dean and her son complained to other nurses and doctors about the unexpected medication. The next day Mrs Dean died at home from heart failure.

Larry Dean knew his mother's death was not of natural causes and complained to the county prosecutor's ofﬁce. An investigation proceeded and a medical examiner and the prosecutor's ofﬁce corroborated Mr Dean's story about the unprescribed medication and identified Cullen as the offender. This investigation represented the chance to stop Cullen in his murderous tracks, yet the drug digoxin was left off the list of medications that her body was tested for. Cullen and other nurses at the hospital were given lie detector tests. When Cullen was arrested in 2003, Warren Hospital was quick to tell the media and investigators that Cullen had passed the lie detector test and that no conclusive evidence had been found to charge him with Mrs Dean's death. Mrs Dean's body was exhumed in 2004 to undergo chemical testing as part of the investigations into Cullen's killings.

In fact, Cullen continued to work at the hospital, and the fact that he been convicted of the harassment of a work colleague and had been suspected of giving a patient unprescribed medication was not even grounds for his dismissal.

Cullen left the hospital under his own steam, and in April 1994, started work at Hunterdon Medical Center in New Jersey as an intensive care unit nurse. Cullen had again placed himself in an environment where he was caring for the most vulnerable of patients.

His divorce had been ﬁnalised the year before and he was able to see his children unsupervised. On the surface, Cullen's life was improving - he had gained a nursing licence to work in the state of Pennsylvania and he had started dating again.

There were more murders in the years between 1993 and 1998 and several incidents where Cullen could have been stopped. In 1997 he was ﬁred from News Jersey's Morristown Memorial Hospital for 'poor performance' and then in 1998 dismissed from Pennsylvania's Liberty Nursing and Rehabilitation Center for 'accidentally' breaking a patient's arm. Cullen, whose mental state was fragile at the best of times, was succumbing to the stressors in his life, which included failed relationships and being forced to declare personal bankruptcy.

At the Liberty Nursing and Rehabilitation Center a nurse took the fall for the death of a patient who, of course, Cullen had murdered, this time with a fatal dose of insulin. Cullen worked at the nursing home for around eight months in 1998. Night- shift nurse Kimberley Pepe was assigned to care for the patient Cullen murdered - an 83-year-old man called Francis Henry. Ms Pepe denied to hospital administrators that she had given Mr Henry any insulin but she pointed the ﬁnger of suspicion at Cullen, who had been caring for the other patient in the room. Ms Pepe was ﬁred from her position at the facility and later ﬁled a lawsuit against the nursing home, which was settled out of court.

The New York Times reported that the nursing home sacked Cullen following the incident where a patient's arm was broken, after Cullen had been seen going into the room of the elderly female with syringes in his hand (she was not injected, but her arm was somehow broken).

Time and time again Cullen was able to gain employment despite his dubious employment record - and always in high- dependency wards such as burns or ICU. At the end of 1998 he took on two jobs - one in ICU at Easton Hospital in Pennsylvania and the other as a night-shift nurse in the burns unit of Lehigh Valley Hospital in New Jersey.

Cullen's killing spree continued and in 1999 at Lehigh Valley Hospital he murdered his second-youngest known victim, 22-year-old Matthew Mattern, with digoxin. Mr Mattern had been severely burned in a car accident. The Philadelphia Inquirer reported that when Cullen confessed to this murder in 2004, he said it was to 'end his [Mr Mattern's] suffering'.

Rumours circulated about Cullen and despite being on the radar of the hospital authorities at several of his workplaces, he would often leave before anything concrete could be discovered about his murders.

St Luke's Hospital in Bethlehem, Pennsylvania, reported Cullen to the state's nursing board in September 2002 - he had killed at least ﬁve patients there over two years - because they were suspicious that he had mishandled medication. Cullen had left the hospital amid growing suspicions of his conduct and the nursing board embarked on an investigation and shared their ﬁndings with police. Nurses who spoke to police shared their grave concerns - proven right - that Cullen was the cause of patient deaths while he'd worked at St Luke's and they were upset that the hospital had allowed him to leave and take up employment elsewhere.

The nurses seemed to play detective more convincingly than hospital authorities or the police and had compiled their own notes and theories about Cullen being a killer: Why did there seem to be more patient deaths when Cullen was on shift? Why had he left so abruptly?

Time and time again investigations of Cullen fell short. No links could be established between deaths of patients and the hospitals where he worked. According to the New York Times 2004 feature article 'Death on the Night Shift', if Cullen's nursing history had been scrutinised then they would have seen that he had been accused of a patient death at one hospital ... implicated in a medical 'mistake' at another. This information should have raised alarm bells and warranted a more thorough look at Cullen. But Cullen had no criminal charges relating to his work or disciplinary actions from state nursing boards so he was able to work unrestricted. New Jersey and Pennsylvania, like many US states, were experiencing nursing shortages in the late 1990s and early 2000s and this made it easier for Cullen to gain employment.

Cullen's last post was his deadliest. He started work at Somerset Medical Center in New Jersey in September 2002. Cullen killed at least 13 patients and attempted to murder two others.

One of the patients murdered by Cullen was the Very Reverend Florian Gall, 68, who had been admitted to hospital with heart disease and other medical problems. Father Gall had been very ill but the priest was making a good recovery. Doctors prescribed digoxin to calm Reverend Gall's rapid heartbeat - a normal use of the drug - and a blood test after his last dose of the drug showed normal levels. Father Gall had started to come out of his drug- induced coma. But on 27 June 2003, Cullen took a dosage of digoxin from a medication cart, slipped into Father Gall's room and injected him with the drug.

When new blood tests showed Father Gall's digoxin levels were almost ﬁve times the normal and safe level, panic mode set in and the hospital tried an antidote to save Father Gall's life. But it was to no avail. The hospital knew Father Gall's death came from a massive overdose of digoxin but did not mentioned this to his loved ones, including his sister Lucille Gall, who was also a nurse. Lucille had spent time with her brother at his bedside and was there as staff tried to save her brother.

Father Gall's family and parishioners were shocked by his death but assumed that ill health and his advancing age were the causes. However, it was Father Gall's death on 28 June 2003 that set Cullen's downfall into motion. Computerised records later showed hospital administrators that Cullen had taken the drug and had also checked the medical records and status of Father Gall.

In his ﬁnal months at the hospital, co-workers reported seeing Cullen in rooms he was not meant to be in and the hospital's computer systems showed that he was accessing records of patients he was not assigned to, as well as requesting medications for patients that had not been prescribed. The New Jersey Poison Information and Education System was ﬁrst to alert Somerset Medical Center that a recent pattern of drug overdose deaths at the hospital could be the work of an employee killing patients.

The hospital pondered this information for several months until October 2003, when it contacted authorities with its concerns about Cullen. In that time Cullen had killed ﬁve more patients and attempted to kill a sixth.

Cullen was ﬁred from Somerset Medical Center in October 2003. Just two months later, Cullen was arrested on suspicion of murder and the whole, terrifying truth of one of America's worst serial killers started to emerge.

Cullen was at dinner with a female friend on 12 December 2003 when police entered the restaurant to arrest him on the suspicion of murdering 68-year-old Reverend Gall.

Cullen was also charged with the attempted murder of 40-year- old Jin Kyung Han, whom he had tried to kill a week before Father Gall. Ms Han had cancer and health problems. She survived Cullen's murderous attempt on her life but she later died of cancer.

Proving the point that 'computers don't lie', it was the computerised drug-dispensing machine at Somerset Medical Center that provided rock-solid evidence for prosecutors that Cullen had administered lethal doses of digoxin to patients. The machine recorded the times and days Cullen ordered the drug, as well as the names of the patients who were supposed to receive it. Somerset County Prosecutor Wayne J Forrest said the data showed that Cullen dispensed digoxin at an 'abnormally high rate' while he was employed at Somerset. The Morning Call newspaper reported on 24 January 2004 that the drug-dispensing machine logs told the Somerset prosecutor's ofﬁce Cullen ordered digoxin for one patient who was not prescribed the drug, took it and then cancelled the order 'in an attempt to conceal his theft of the drug'.

To dodge the death penalty, Cullen agreed to plead guilty and help authorities in New Jersey and Pennsylvania identify all his victims. Investigators say they will never know how many people Cullen really killed. His memory was sketchy and some hospitals he had worked at had destroyed records that may have revealed more victims. By Cullen's own recollection he killed at least 40 people.

His youngest known victim was murdered at Somerset in May 2003 - 21-year-old Michael Strenko. Michael, a star athlete, had a blood disorder and was in hospital for a spleen transplant. Though it was a serious procedure, Michael was expected to make a full recovery.

A heart-wrenching memorial website made by Michael's parents shows baby pictures and the promising life of the young man who was cruelly killed by Cullen in a place where he should have been safe.

Michael's father, Thomas Strenko, was one of the many loved ones of Cullen's victims who spoke at his sentencing hearing on 2 March 2006.

'For someone to be able to hop from hospital to hospital with these problems for over 15 years deﬁes trust,' Mr Strenko said. 'We are outraged that no one stopped Charles Cullen from murdering my son.'

In a disturbing and deeply distressing scene for the victims' families, Cullen broke his silence of the previous years and started rambling and repeating over and over again, 'Your honour, you need to step down.' He kept chanting the words, despite the judge telling him to stop. Even a white cloth gag with duct tape ﬁxed over it failed to stop Cullen shouting. He kept going for 30 minutes while families were reading out their impact statements.

In another bizarre twist that threatened the justice process, Cullen, who was responsible for taking the lives of so many people, then decided to try and save one.

In August 2006, he donated one of his kidneys to Ernie Peckham, the brother of a former girlfriend. Peckham's mother wrote to the serial killer, begging him to help her son. Cullen had once lived with Peckham's sister Michelle, and he was determined to be a match to donate. Cullen's lawyer, Johnnie Mask, said the kidney donation was a way for his client to 'atone for his sins'.

So determined was Cullen to donate his kidney that he threatened to stop cooperating with the detectives who were investigating his crimes that stretched back to the 1980s. The

families of Cullen's victims saw this as blackmail and cowardice on the part of the killer who said he would not appear at his sentencing if he were denied the right to surgery to help Mr Peckham. After a series of meetings, New Jersey Attorney General Peter C Harvey agreed to let Cullen have the surgery but only after he appeared at his sentencing hearing.

'We are victim-focused and have factored in the feelings of the families of the murder victims who are angry and still grieving,' Mr Harvey said. 'They [the families] want the court and Cullen to know how much they hurt.'

At the sentencing hearing, as well as interrupting the judge with his rambling, Cullen would not look at any of the families of his victims, as they tearfully and angrily spoke of their pain at losing their loved ones.

'Charles, why don't you look up at us?' yelled one mother as she clutched a photo of her son in his cofﬁn.

'I want you to die tomorrow so you can meet God tomorrow because you know what? There ain't no doors out of hell, babe,' called the granddaughter of victim Mary Natoli. Deborah Yetter-Medina labelled Cullen 'Satan's Son' for murdering her grandmother, who had dementia and was being treated for anxiety when she was killed.

Cullen was sentenced to 11 life sentences without parole for his 'cowardly crimes'. 'Satan's Son' will live the rest of his life behind bars.

In 2009, he received his twelfth life sentence for the 1998 murder of retired Pennsylvania steelworker Ottomar Schramm, whom Cullen killed with an overdose of digoxin at Easton Hospital.

Charles Cullen's crimes led people to question how he could have worked at so many hospitals. Cullen was never given a bad employment reference, nor was information shared that he was under investigation or ﬁred from different hospitals.

A major ﬂaw in the system of healthcare recruitment was revealed during the investigation. There were not adequate and legal ways for employment checks to be undertaken by healthcare facilities into the people that they hired. Nor were there reporting requirements or legal protections for employers who suspected a healthcare worker of negligence, misconduct or worse. If any of the places that employed Cullen had the legal ability to check with his former workplaces then they would have discovered that he had been under investigation or had been ﬁred, which could have stopped his murder spree.

In New Jersey, the Health Care Professional Responsibility and Reporting Enhancement Act (also known as the Nurse Cullen Act) became law in 2005 as a direct response to the serial killings. The act requires healthcare professionals and bodies to notify the New Jersey Division of Consumer Affairs if they have information about incompetence, impairment or negligence of a healthcare worker. The act also means criminal background checks of healthcare workers seeking licence to work in New Jersey is mandatory.

There has been criticism of this act among healthcare professionals in New Jersey who say it is too extreme and people's careers can be ruined by a legitimate mistake or a simple lack of experience.

In 2013, the American television program 60 Minutes secured an exclusive interview with Cullen. It was the ﬁrst the award- winning news show had ever interviewed a serial killer and veteran correspondent Steve Kroft interviewed Cullen, who appeared nervous and pathetic behind a glass barrier.

Recalling the interview for the program's online extra 'Correspondent Candids', Kroft said he wasn't sure Cullen would even answer any of his questions.

Producer Graham Messick said Cullen was the 'ultimate insider threat'.

'It takes a really subversive, devious mind to sort of break all the rules and actually use that to commit the worst crime of all, to kill people,' Messick recalled.

During the interview, Kroft asked Cullen if he got pleasure from killing people.

'No, I thought that people weren't suffering anymore. So, in a sense, I thought I was helping,' Cullen answered.

Kroft said that many of the victims were expected to recover and were not in pain and Cullen replied, 'You know, again, you know, I mean, my goal here isn't to justify ... You know what I did there is no justiﬁcation. I just think that the only thing I can say is that I felt overwhelmed at the time.'

Somerset nurse and Cullen's closest friend at the hospital, Amy Ridgeway was also interviewed for the program and told Kroft that at ﬁrst she couldn't believe Cullen had done anything.

'He was always early, always on time, crisp. Very serious about getting to work,' Ms Ridgeway recalled.

She said she had considered him a good nurse but when she was confronted by investigators about the evidence, his real employment history and the damning drug printouts that showed Cullen had been taking deadly drugs from the computerised dispenser, the truth could not be denied.

It was at this point a devastated Ms Ridgeway knew her friend was killing people and she offered to help the police. Ms Ridgeway was crucial in helping police to obtain a confession from Cullen. She recalled that she lied to Cullen and told him that investigators were also looking at her as a suspect in the killings.

'What did you say to get him to confess?' Kroft asked Ms Ridgeway.

'I wasn't very honest with him and there's a part of me, I still feel guilty about that. I was manipulating him a bit. I told him the investigators were also looking at me and how could he think that I wasn't somehow going to be implicated,' she said.

'I remember saying to him, "Who was your ﬁrst victim?" ... He started to talk and said it was a long time ago.'

Journalist and author Charles Graeber, who wrote the deﬁnitive book on Cullen called The Good Nurse: A True Story of Medicine, Madness, and Murder, said, 'We'll never know how many people Charlie Cullen killed.'

'I would be very surprised, as would pretty much everyone I have spoken to with any knowledge of this case if it was not in the hundreds, multiple hundreds,' Graeber said.

During the 60 Minutes interview, Cullen said he was sorry for his crimes but added chillingly, 'Like I said, I don't know if I would have stopped.'
Extract from Angels of Death - Disturbing Real-life Cases of Nurses and Doctors Who Kill. Published by The Five Mile Press Pty Ltd © Emily Webb. Published January 2015 RRP A$32.95 Available in leading bookshops and mass market retailers

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new jersey poison information and education system

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people for the ethical treatment of animals

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HIS job was to look after the sickest of the sick. People recovering from horrific burns and life-threatening illnesses. But 'Satan's Son' betrayed their trust in the greatest way imaginable murdering dozens of patients. Emily Webb tells his story in a new book.

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How THC Replaces Your Brain's Neurotransmitters

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Entrevista a Joana Santos, técnica de propagação de canábis medicinal, Tilray Cantanhede

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Questões-chave acerca do processamento da Cannabis numa empresa farmacêutica pioneira global na produção, investigação e desenvolvimento de preparações e substâncias à base da planta da canábis para fins medicinais.

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Can Psychedelics Make You Less Depressed?

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Lysergic acid diethylamide, também conhecido como LSD, é um composto sintetizado pela primeira vez em 1938 por Albert Hofmann, mas só passados 5 anos é que se descobriu o seu efeito quando o próprio Dr. Hofmann consumiu uma quantidade desconhecida de LSD por acidente. É também um agonista de recetores de serotonina mas muito mais potente que os anteriores (0.1 mg de LSD correspondem, aproximadamente, a 10 mg de psilocibina ou 300 mg de mescalina). Nas doses corretas, este composto pode ter efeitos terapêuticos em diversas condições neuropatológicas, como vários tipos de depressões e síndromes de ansiedade, stress pós-traumático, bipolaridade, défice de atenção e hiperatividade, algumas doenças no espetro do autismo e dependências (tabaco, álcool, canábis, cafeína e vários fármacos de atuação no sistema nervoso central).

Fonte: Ona G, Bouso JC. Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review. Neurosci Biobehav Rev. 2020;119(September):194-203. doi:10.1016/j.neubiorev.2020.09.035

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