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RESEARCH PROJECT PROPOSAL

7 Year (2015 to 2022) Commercial Trial

Determining key factors for commercializing medicinal cannabis

A proposal submitted to Medicines Control Council (MCC)

Department of Health (DOH)

A joint Proposal submitted by House of Hemp Holdings (Pty) Ltd in partnership with IKS Research Unit, Dept. of Pharmacology, University of Free State (UFS). AUTHORISING SIGNATURES Prepared by House of Hemp:

Checked by University of Free State:

Name and Designation:

Dr. Thandeka R. Kunene Dr. Motlalepula G. Matsabisa

Signature:

Name and Designation

Ms. Leanne Blumenthal Ms. Miranda Javu

Signature:

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This 7 Year (2015 to 2022) Commercial Research project is supported by the following Government departments and agencies:

1. Department of Science and Technology. 2. Department of Trade and Industry.

Please see the Appendix D for copies of the two letters of support. 3. Department of Agriculture, Forestry and Fisheries 4. C.D.A. – Central Drug Authority 5. C.S.I.R. ( Council for Scientific and Industrial Research) 6. N.A.M.C (National Agricultural Marketing Council) 7. A.R.C ( Agricultural Research Council) 8. Ingquza Municipality Lusikisiki (Eastern Cape) 9. EThekwini Municipality Durban (Kwa Zulu Natal) 10. Industrial Development Cooperation

Letters of support and MOAs describing professional relationships are available upon request. The following universities have agreed to collaborate, supervise and assist with research objectives:

University of Free State University of the Witwatersrand University of Cape Town University of Natal Fort Cox Agricultural College

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Table of contents

ACRONYMS: 4

SECTION 1: INTRODUCTION TO CANNABIS 5 Cannabis used for medical purposes 5 Cannabis in Africa 7 Cannabis in Asia, Europe, Middle East and America 8

SECTION 2: BACKGROUND OF THE SA MEDICAL CANNABIS STUDY 9

SECTION 3: THE APPLICATION 12 The proposal 13 Problem Statement 13 Research Objectives 13 Activities to be undertaken 14

Activity 1: Literature Research 14 Activity 2: Geographic indicators research 14 Activity 3: Seed breeding pilot 15 Activity 4: Cultivating Pilot 15 Activity 5: Pharmacology compounds 15 Activity 6: Extraction of compounds 17 Activity 7: Conversion into end products 17 Activity 9: Clinical Studies 18 Activity 9: Marketing 21 Activity 10: National Medical Cannabis Access Program 22

SECTION 4: PERMITS NEEDED 23

DETAILS OF THE PROPOSED PROCESSES 23 Operational plan 23 Cultivar names 24 Area expected to be planted 24 Materials to be harvested and transported 25 Security Measures 26 Notification of local security officials 28 Security Tracking System 28 Analysis and Record Keeping 28 Reporting 29

SECTION 5: IMPLEMENTING TEAM 30 APPENDICES

Appendix A: Reference list Appendix B: 4 Application forms for 4 Coordinators and 4 site managers Appendix C: Exact Geographical location – Dube Port; GPS coordinates and Site Map Appendix D: Exact Geographic location – Lusikisiki: GPS coordinates and Site Map Appendix E: Letters of support from the DTI and the DST.

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ACRONYMS:

- ARC: Agricultural research council - CBD: Cannobidiol - CDA: Central Drug Authority - CSC: Cannabis Steering Committee - CSIR: Council for Scientific and Industrial Research - DAFF: Department of Agriculture, Forestry and Fisheries - DEA: Department of Environmental Affairs - DOH: Department of Health - DST: Department of Science and Technology - DTI: Department of Trade and industry - EC: Eastern Cape - EDD: Department of Economic Development - GAP: Good Agricultural Practises - HOH: House of Hemp - HRD: Human Resource Development - IKS: Indigenous Knowledge systems - KZN: KwaZulu Natal - MCC: Medical Control Council - NAMC: National Agricultural Marketing Council - NHCF : National Hemp and Cannabis Foundation - NMCAP: National Medical Cannabis Access Program - NMCRI: National Medical Cannabis Research Institute - RDI: Research, develop and innovate - SAPS: South African Police Services - THC: 9 Delta Tetra HydroCannabinoids - UFS: University of the Free State - WC: Western Cape - WHO: World Health Organisation

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INTRODUCTION

This proposed research study is as a result of a Medical Cannabis Research program set up by the Department of Science and Technology on request by the Parliamentary Science and Technology Portfolio Committee that recommended a detailed research, development and innovative study of how South Africa can increase its access to medicinal cannabis for sick people in-line with global trends. This is to be done in a manner, which will ensure quality, safety, efficacy and more importantly control of the (currently) illegal substance to be effectively regulated within a framework of strict legal controls. This request by the Parliamentary committee was a response to the late IFP M.P. Ambrosini proposed Medical Innovation Bill of 2014. At the same time, the Department of Trade and Industry has partnered with the Department of Science and Technology to ensure that this study leads to the commercialization of the research results. Thus the study aims includes determining the factors/variables that will influence the commercialization of cannabis cultivation and processing in South Africa for improved quality of life and sustainable livelihood. Activities of the study include the investigation of how the emerging legal Medical Cannabis industry will benefit poor rural areas and ensure substantial involvement of indigenous Knowledge holders/practitioners that have traditional claims to Cannabis. Furthermore this study is in line with one of the key recommendations of the 2015 National Hemp Foundation Report (NHF) that concluded that the NHF should also include research for medicinal cannabis applications due to the presence of Cannabinoids (CBD) in the hemp crops. Thus, this proposal further serves to extend into Phase 3 the research study commissioned by the government driven NHF that started with Phase 1 (agronomic feasibility) that was conducted from 1999 to 2005 and entered into phase 2 (commercial feasibility study) that was conducted from 2009 to 2015. This proposal is divided into five sections, namely:

1. Introduction to cannabis; 2. Background to the South African Medical Cannabis Research Study; 3. The application including the proposed research study objectives aims, objectives and activities to be

undertaken; 4. Requirements from the permit based on activities to be undertaken as well as arrangements to ensure

adherence and compliance to permit conditions; and 5. Implementing team and partnerships

SECTION 1: INTRODUCTION TO CANNABIS The Cannabis Sativa L plant family has been used for many centuries as a source of fibres, seed-oils and medicines. Despite its many uses, the cannabis family was banned in 1928 due to high THC content of Cannabis Sativa plants (commonly known as dagga in South Africa). However, the early 1990’s saw renewed global interest in cannabis as ecological regulatory policies and tax incentives increasingly favoured natural and environmentally friendly produce and with most EU governments researching and cultivating cannabis for medical and industrial/commercial purposes. More than 30 countries have adopted industrial hemp as an established agricultural commodity. More than 27 countries have decriminalized the medical uses of cannabis. This proposed research study is focused on the medicinal uses of cannabis. Cannabis used for medical purposes

There have been many claims internationally as to what diseases medical cannabis can be used as cure. In putting together this proposal the research team conducted a limited pre-study literature search to get a glimpse of the existing research and potential new research related to cannabis for medicinal uses. This limited literature search

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indicated that there is a vast amount of credible scientific journals that published papers, conferences proceedings, books and references which document clinical research that reveals numerous pre-clinical and clinical studies demonstrating cannabinoid’s ability to be effectively used in the many diseases listed below. First a brief discussion on the 10 priority diseases of South Africa that were cited in the limited literature as being positively affected by cannabis:

Priority disease as identified SA government Notes on the disease and research interest

Cancer (breast; colorectal; brain; leukemia; lung; melanoma; oral; pancreatic; prostate; Skin; Testicular) and oncology

Literature demonstrates ca combination of cannabinoids have the ability to act as antineoplastic agents on gliomas cells (an especially aggressive malignant form of cancer). Cannabinoids have also been reported to inhibit growth of gliomas cell lines and of gliomas tumor in humans. Some experts now believe that cannabinoids may represent a new class of anticancer drugs that have antitumor properties and thus retard cancer growth, inhibit cell proliferation, invasion, angiogenesis and metastatic spreading/migration of cancer cells in tumors that highly resistant to current treatments.

Gastrointestinal system disorders (irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, metabolic syndrome).

Many experts believe that cannabis and its compounds represent a novel therapeutic approach for treatment of numerous gastrointestinal (GI) disorders. Cannabis suppresses gastrointestinal motility, inhibits intestinal secretion, reduces acid reflux, and protects from inflammation, and promotes epithelial wound healing in human tissue.

Hepatitis and other diseases of the liver (hepatitis, fibrosis, steatosis, ischemia-reperfusion injury and hepatic encephalopathy.

Hepatitis C is a viral disease associated with fatigue, depression, joint pain, liver impairment including live cancer. Patients diagnosed with Hepatitis C frequently report using cannabis to treat both the symptoms and the nausea associated with the antiviral therapy.

HIV / AIDS related Literature reveals that cannabis represents another treatment option, as it is said to decrease HIV replication and aid in treating symptomatic treatment as a result of decrease in HIV replication as well as side effects of various antiretroviral medication. A recent study reported that more than 60% of HIV/AIDS patients self-identify as “medical cannabis users”. These users are 3.3 times more likely to adhere to their antiretroviral regimes and it has effectively being used in HIV/AIDS side effects such as wasting.

Hypertension Literature reveals that increased blood pressure following abrupt cessation of daily cannabis. Therefore Cannabis is used in management of hypertension. However, some review of the research literature concerning some biological and physiological effects of cannabis claim that smoking of cannabis in high doses increases the work of the heart by increasing heart rate, and in some cases by increasing blood pressure. This contradiction opens an opportunity for further research to study the effects of Cannabis on hypertensive individuals.

Nausea and vomiting (resulting from chemotherapy, radiotherapy, HIV combination therapy and Hepatitis C medication)

Medical cannabis is said to be more effective in chemotherapy-induced nausea and vomiting. Also caution against long-term cannabis use that may cause nausea and vomiting, a condition known as cannabinoid hyperemesis syndrome. This contradiction opens an opportunity for further research to study the effects of Cannabis on nausea and vomiting.

Neuropathic pain, neuro-degeneration and movement disorders (including Dystonia, Huntington’s disease, Parkinson's disease, Tourette's syndrome, multiple sclerosis, epilepsy, Alzheimer’s disease).

Cannabis has proved effective in treatment of symptoms and progression neurological problems, especially in cases where other treatments have not been effective. There is a significant amount of research that validates the use of cannabis in these diseases.

Obesity and Diseases of pancreas (Metabolic syndrome, obesity, diabetes, pancreatitis)

A study published in the American Journal of Epidemiology found a correlation between cannabis use and body weight. In another large study conducted by GW Pharmaceuticals and the University of Buckingham recently found that some compounds found in cannabis can have a beneficial effect for people suffering from metabolic diseases associated with obesity and diabetes. In animal studies these compounds have been shown that they acted as appetite suppressants, lowered cholesterol, decreased fat buildup and improved insulin sugar response.

Pain - (Acute Pain, Experimentally-induced acute pain, Chronic Pain; Neuropathic pain or chronic non-cancer pain; Headache and migraine, palliative treatment of cancer and AIDS to decrease pain; intractable pain

Cannabis appears to be somewhat effective for the treatment of chronic pain particularly in the treatment of pain resistant to conventional pain therapies. Studies argued on the safety of using cannabis for palliative care especially with the increase of physicians prescribing cannabis for pain.

Psychiatric disorders (Anxiety attacks, depression, post-traumatic stress disorder, psychosis; schizophrenia, dementia , other mental disorders).

Some writers have claims that taking cannabis leads to acute adverse mental effects in a high proportion of regular users and that these adverse effects are not uncommon and they are generally short lived, but may recur with continued use of the drug.

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Over and above the SA priority diseases the following have been cited to be positively affected by Cannabis:

ADD/ ADHD Addiction risk- Physical Alcoholism and opioid withdrawal symptoms ALS Alzheimer’s Amotivational Syndrome Appetite Stimulant Arthritis AND Musculoskeletal Disorders

(Osteoarthritis, Rheumatoid Arthritis, Osteoporosis, osteogenesis)

Asthma Atherosclerosis Atrophie Blanche Autism Bowel disease Cerebral and myocardial ischemia and diseases

of the liver (hepatitis, fibrosis, steatosis, ischemia-reperfusion injury and hepatic encephalopathy).

Chronic Cystitis Congestion Convulsion Cough Dementia Dermatitis Dystonia Eating disorders or anorexia.

Epilepsy Familial Mediterranean Fever Fertility Fever Fibromyalgia Glaucoma Heart Disease/ Cardiovascular Herpes Hiccups Huntington’s Disease Hysterectomy Idiopathic Intracranial Inflammation; Inflammation, inflammatory skin

diseases (dermatitis, psoriasis, pruritus) Insomnia Sleep disorders, sleep disturbance. Lupus, an autoimmune disorder. Meige’s Syndrome Migraine/ Headache MS Multiple sclerosis Osteoporosis Parkinson’s Disease Post Traumatic Stress Disorder Pruritis Sickle Cell Disease Spasticity Spasticity disorders (multiple sclerosis,

spinal cord injuries, or spinal cord disease Spinal Cord injury Stroke

See the Appendix A that lists the clinical studies cited in the relevant research done to date. Pre-research studies has collected this list but only studied a few. We are including this list here to indicate how much work has already been done and this study will analyze and summarize research done already and identify research gaps. There is documentary evidence that Cannabis has been successfully used for thousands of years globally. Cannabis in Africa

Cannabis has been identified as a wild growing weed that was freely rooted in the pre-colonial period in many places in Africa including Egypt, Ethiopia, Zambia, Zimbabwe, Lesotho, Malawi, Mozambique and Swaziland, Cameroon, Morocco and South Africa. Cannabis has been recorded to be use in many African countries for traditional worship and healing rituals. There are many anecdotal recordings of Cannabis used to heal the following: anthrax, asthma, antidote for blood poisoning, cancer, dysentery, fever, malaria, pain of hemorrhoids, relieving inflammation, to facilitate childbirth and treating snake bites. In South Africa, cannabis is said to be an integral part of many indigenous communities including the Pondos of Lusikisiki in the Eastern Cape, Waterberg – Vhenda people in Waterberg, the Ndwandwe and Amathonga in KwaZulu-Natal. In all provinces some traditional healing practitioners use cannabis in their treatment protocols.

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The use of Cannabis for worship purposes has been recorded with the Khoi San who use cannabis for psychoactive relieve during their nocturnal healing dances and the RasTafari who use Cannabis as their Holy Sacrament.

In 1958 Prof. Frances Ames, completed her research and published her work in the British Journal of Psychiatry motivating for the therapeutic benefits of cannabis particularly for people with multiple sclerosis. Cannabis in Asia, Europe, Middle East and America

The botanist Li Hui-Lin wrote that “in China, the use of Cannabis in medicine goes back to thousands of years ago. Chinese Emperor Shen-Nung, who was also a pharmacologist, wrote a book on treatment methods in 2737 BCE and recommended cannabis for many ailments, including constipation, gout, rheumatism, malaria and absent-mindedness, poor memory. Cannabis is one of the 50 “fundamental” herbs in traditional Chinese medicines.

Texts from ancient India confirm that cannabis' psychoactive properties were recognized, and doctors used it for treating a variety of illnesses and ailments, including insomnia, headaches, gastrointestinal disorders, and pain, including during childbirth.

In the medieval Islamic world, Arabic physicians made use of the diuretic, antiemetic, antiepileptic, anti-inflammatory, analgesic and antipyretic properties of Cannabis and used it as medication from the 8th century. In Syberia cannabis seeds were found dating back to 3000BC. The Ancient Greeks are said to have used cannabis to dress wounds and sores on their horses after battle. The plant was also given to humans for a variety of ailments, including ear pain, inflammation, nose bleeds and expelling tapeworms. In the 1830s, an Irish physician by the name of William Brooke O’Shaughnessy observed the use of medical cannabis during a trip to India and introduced cannabis to physicians as treatment including muscle spasms, rheumatism, epilepsy, stomach cramps and pain. Recently in the UK, GW Pharmaceuticals was conducting clinical trials at the St James University Hospital in Leeds.

In 1963, an Israeli Scientist Raphael Mechoulam, known as the patriarch of cannabis science, worked at the Weizmann Institute of Science and named the cannabis chemical composition which he called THC (tetrahydrocannabinol) and the CBD (cannabidiol) and Israeli has become one of the most advanced medical cannabis research and development program. The United States Pharmacopeia (USP) provides a list of acceptable medical products each year, and cannabis was recognized in many of its earliest editions. In 1964 Albert Lockhart and Manley West developed the pharmaceutical "Canasol" cannabis extracts and in 1987 gained permission to market it. In the 1970s, a synthetic version of THC, Marinol, was produced and approved for use in the United States as a medicine. By September 2015, 23 states of the USA had legalised or decriminalised the use of medical cannabis.

Today there are more than 20 countries who have legally allowed for the use of Cannabis for medical applications include Argentina, Australia, Belgium, Canada, India, Iran, Jamaica, Brazil, Mexico, North Korea, Colombia, Costa Rica; Pakistan; Spain , Czech Republic, Switzerland, Ecuador, France, 23 states of United States of America, and Uruguay. Cannabinoids that are currently on the market in the USA and Europe include:

HU-211 (Dexanabinol) which is used to treat endotoxic shock, ischaemia and head trauma Nabilone (Cesamet®) is a schedule 7 substance in South Africa and a synthetic copy of THC used to treat

pain and nausea. It was also sold in Canada, Australia, United Kingdom and Ireland, but not as a drug of first choice.

Dronobinol (Marinol®) is a cannabinoid prescribed as an appetite enhancer primarily for people who have HIV/AIDS, people being treated with chemotherapy and gastric bypass patients. It has the appearance of brown oil and is administered in glycerin capsules of 2.5, 5 and 10mg. It is marketed in the United States,

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Canada, South Africa, Australia and New Zealand. It is a schedule 6 substance in South Africa but not a drug of choice. It seems to be a last resort.

Sativex is a nasal spray that is used to alleviate neuropathic pain and spasticity in multiple sclerosis patients.Unlike Cesamet® and Marinol®, Sativex® is not a synthetic cannabinoid, but an extraction of a selected phenotype with a number of known, standardized and homogeneous cannabinoids, which basically contains delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). A dose of 0.1 ml contains 2.7 mg of THC, 2.6 mg of CBD and 5% of other cannabis derivates. It is administered sublingually by spray-application, and it is sold in bottles of 5, 5 ml with 51 applications. It was patented by the British laboratory GW Pharmaceuticals at the beginning of the last decade and marketed by Bayer and Laboratories Almirall.

Rimonabant which is an appetite suppressant used to decrease the appetite in Cannabis smokers While some of these medicines are registered with South African MCC and are distributed in South Africa; the country is not producing these compounds and there are no initiatives towards product development and innovation; yet cannabis crops exist in South Africa in abundance and many tribes consider Cannabis as indigenous. . In South Africa; Cannabis is currently listed as a schedule 7 product in the Schedules of the Medicines and Related Substance Act, Act 101 of 1965 as such unless specified in Schedule 6: It can be seen here that dronabinol which is listed as a schedule 6 substance is excluded.

Because of it’s up scheduling it is therefore not a banned substance and available in South

Africa. It is important to note that the big pharmaceutical companies have been buying up patents on synthesized Cannabinoids for decades. However, due to the massive complexity of the molecules involved and the complex system of interaction between the components, as well as the human body’s ability to synthesizes them (the endo-cannabinoid system), it is impossible to recreate synthetically what is already available through nature in pure perfection in the raw plant. Synthetic Cannabinoids have proved to be disappointing facsimiles to date. SECTION 2: BACKGROUND OF THE SA MEDICAL CANNABIS STUDY

On the 18th February 2014 the late Dr. Mario Oriani Ambroisini (IFP Member of Parliament) introduced the Medical Innovation Bill (Government Gazette, notice 100 of 2014; number 37349) to “... make provision for innovation in medical treatment and to legalize the use of Cannabinoids for medical purpose and beneficial commercial industrial uses…”. Key features of the Medical Innovation Bill include the following:

• Allow medical doctors and pharmaceuticals to grow and distribute Cannabinoids. • Code best practices in line with international standards. • Clinical trials for selected illnesses with volunteers.

“Cannabis (dagga), the whole plant or any portion or product thereof, except: a. when separately specified in the Schedules; (S6) or b. processed hemp fibre containing 0,1 percent or less of tetrahydrocannabinol and products manufactured from such fibre,

provided that the product does not contain whole cannabis seeds and is in a form not suitable for ingestion, smoking or inhaling purposes; or

c. Processed product made from cannabis seeds containing not more than 10 milligram per kilogram (0,001 percent) of tetrahydrocannabinol and does not contain whole cannabis seeds. ["Processed" means treated by mechanical, chemical or other artificial means but does not include - (a) harvesting; or (b) the natural process of decay"].

Synthetic cannabinoids (synthetic substances with cannabis-like effects), including but not limited to cannabicyclohexanol, tetrahydrocannabinol and their alkyl homologues, except: when separately specified in the Schedules; dronabinol ((-)-transdelta-9-tetrahydrocannabinol), when intended for therapeutic purposes; (S6) in hemp seed oil, containing 10 milligram per kilogram or less of tetrahydrocannabinols, when labeled "Not to be taken" or

"Not for internal human use"; or In products for purposes other than internal human use containing 10 milligrams per kilogram or less of tetrahydrocannabinols.

[“Hemp seed oil” means the oil obtained by cold expression from the ripened fruits (seeds) of Cannabis sativa.]

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• Afford medical practitioners discretion on prescriptions. • Allow pharmaceuticals to develop innovative products • Include existing commercial and industrial uses. • Cater for Medical Tourism.

The bill has received wide support from the ruling party with the President Zuma announcing that he has asked the Minister of Health to investigate how to ensure that the sick have access to quality cannabis. The Minister of Health tasked the Parliament Portfolio committee on Science and Technology with research towards decriminalizing medical cannabis to ensure the access of Medical Cannabis to those sick people who needed it at the same time ensure there are controls to ensure safety and efficacy. The media reported that this move has been welcomed by many including; doctors, patients, cancer associations, HIV treatment campaign, traditional healers, traditional leaders, spiritual groups like the Rastafari, political parties and individuals. All agree that “With the Medical Innovation Bill, it seems potential exists for the beneficiation of the SA natural resource (Cannabis) to produce export marketable high-value niche medicinal products; unlock the down-and-upstream value added enterprises plus create the associated employment and income generating opportunities in the communities that have been growing Cannabis as part of their rituals, customs, traditions and culture”.

However, as it is, the Ambrosini submission proposes that the Medical Innovation Bill DOES NOT have to be referred to the National House of Traditional Leaders since it does not contain provisions pertaining to customary law, customs or traditional communities!!!

This poses a socio-political threat that could see the previously disadvantaged traditional cannabis growing communities being excluded in the emerging medical cannabis industry while the historical advantaged businesses (who have been traditionally snubbing the Cannabis plant) get to benefit. This is clearly undesirable as it will undermine and set back government’s efforts to position the rural African farmers into the 1st economy.

However, if these disadvantaged communities are given an opportunity to participate as the primary drivers and beneficiaries of the cannabis industry; they can use their existing indigenous knowledge and skills to explore the commercial opportunities embedded in the emerging cannabis industry thereby transforming their illicit livelihoods into 1st economy participants.

The greatest barrier to a rural area based cannabis industry is the drug trafficking and illicit industry. According to Interpol, South Africa is in the top four countries that are a source of herbal cannabis. South Africa’s cannabis herb seizures accounted for almost 68% of all cannabis herb seizures in Africa. At the global level, South Africa’s cannabis herb seizures were almost 16% of the world total. In the year 2000, South Africa (718 metric tons) ranked second behind Mexico (2,050 metric tons) in terms of cannabis tonnage seized. In Africa, only Malawi (312 metric tons) and Nigeria (212 metric tons) came close. These figures if turned into an economic opportunity through the legalization of cannabis, and the relaxation of production limits to (at least 30ha commercially grown); this means South Africa has the potential to lead this field and dominate the global markets. To this end there was an urgent appeal for intervention by the Government to come up with ways to ensure that the indigenous Cannabis communities also benefit from the emerging cannabis industry; in-line with many countries globally who are Innovating, beneficiating and commercializing cannabis industry to their benefits.

The current restrictive legislative environment in South Africa prevents new idea generation, research development, innovation, product development, technology transfer, beneficiation, manufacturing and commercialization of cannabis based products. South Africa is therefore unable to realize the economic, health and social benefits that could arise from the research and industrialization/commercialization of SA cannabis.

Controlled scientific and IKS research can assist to influence policy direction on Cannabis and such polices would aid government develop policies and regulations that are favourable for the use of Cannabis, especially for medical purposes. The policy change could also empower indigenous knowledge holders and indigenous

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communities of practice to commercialize their existing IKS based cannabis knowledge to innovate, benefit and thus improve quality of life and sustainable development; especially in South African rural areas.

Thus the DST and the DTI joined forces to ensure that the commissioned research also investigated means of ensuring a substantial involvement of these areas and indigenous knowledge and systems (IKS) holders in the research study and the envisaged commercialization. The DST-DTI Cannabis Initiative

Department of Science and Technology in collaboration with the Department of Trade and Industry commissioned a medical cannabis research study as part of Presidential commitment to Parliament to increase access to sick people and to investigate ways of ensuring that indigenous communities of practice also benefit from the emerging medical cannabis industry. The outcome of this medical cannabis research would be to establish regulated Ubuntu based cultivation and manufacturing industries to support an ongoing and reliable supply of medicinal cannabis for patients; globally. Also, it was deemed important to qualitatively and quantitatively study South African Cannabis species and ascertain whether geographical differences may impact on the quantity and quality of plant compounds and the related pharmacological response of South African community to cannabis as a medicine. Thus, such a study would include a systematical collection of samples and data on the existing South African cannabis and to scientifically validate the traditional claims of medicinal uses attached to local cannabis. Research study results will assist in advising patients of any health benefits of cannabis but also more importantly dismiss any anecdotal myths of the benefits of the use of the plants and discourage its use where there are no benefits, or if adverse side effects and toxicities are indicated.

Finally, the research study will include detailed appropriate clinical trials to prove/disprove anecdotal theories on medical cannabis use and will focus on a range of conditions and symptoms that are prevalent in South Africa. The research study and its clinical trials will act as a pilot to test and optimize design and institutional arrangements for implementing a National Medical Cannabis Program (NMCP) to facilitate patient access to Cannabis.

To this end, the DST appointed The University of Free State (UFS) and the House of Hemp (HoH) to implement this medical cannabis research, innovation and development part study, while the DTI has committed to fund and or lobby for funds for the setting up a medical cannabis commercial agro-hub pilot in indigenous community areas.

This study will be linked to the existing National Hemp Foundation (NHF) Research Program that is investigating the amendment of the 3 laws that restrict the cultivation, possession and use of Cannabis including: 1. The Drugs and Drug Trafficking Act, 1992 (Act No. 140 of 1992) enforced by the SAPS; 2. Amendment of Medicine & Related Substances Act, 1965 (Act No. 101 of 1965) enforced by the Department

of Health; and 3. The Environmental Conservation Act, 1989 (Act No. 73 of 1989) enforced by the Department of Environmental

Affairs. The 6 October 2014 cannabis steering committee meeting, made of mainly key government stakeholders; on the, it was resolved that research on Cannabis for medical applications should be included as a natural expansion of the current National Hemp Foundation program. This proposal meant the National Hemp Foundation would be renamed as National Hemp and Cannabis Foundation (NHCF) with two research streams namely industrial cannabis (hemp) and medical cannabis (cannabis).

Please refer to past minutes of the NHF (2009, 2010, 2011, 2012, 2013, 2014) as well as parliamentary meeting outcomes (18 Feb 2014) and the notes coming out of key stakeholders meetings around Medical Cannabis Research study (July 2014, October 2014 and September 2015). Also refer to the proposal and research contracts that were approved by the DST for the 5 year medical cannabis research study.

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SECTION 3: THE APPLICATION

This proposal is jointly submitted and to be implemented jointly by University of Free State (UFS) and House of Hemp Holdings (HoH), co-coordinators that have been appointed by the DST to implement the Medical Cannabis Research Study. UFS and HoH partnership has all the necessary legal permits know-how; compliance; expertise and networks to make this proposed research project successful.

1.1. UNIVERSITY OF FREE STATE (UFS) The UFS has expertise in traditional medicines health research and in the pharmaceutical development of traditional medicinal products. The team has expertise in Pharmacology (laboratory and clinical pharmacology) basic pharmacological drug development and testing, toxicology, clinical trials and clinical research, chemists, pharmacists, social scientist with medical anthropology expertise, and expertise in medicines regulation. The following will be the coordinators of the UFS Cannabis Research team:

Team member Envisaged role Dr. Motlalepula Gilbert Matsabisa Project Leader and PI – Overall Project management. In the lab for method development, and to give research

direction. Project accountability, Project Financial accountability and management, liaise and report to funders and to UFS on the project. Coordination of all RDI project activities and reporting.

Ms. Mirranda Thobela Javu Community liaison, community training, field trips IKS documents translations and documentation

UFS role is to analyses collected samples, develop extraction technologies, end products as well as coordinate clinical trials to be undertaken in collaboration with other institutions locally and internationally.

1.2. HOUSE OF HEMP (HOH)

House of Hemp has expertise in industrial cannabis (hemp) that coordinated the Human Resource Development (HRD) of the NHF’s first phase and s the only private sector company to be granted legal permits by the Department of Health to coordinate the National Hemp Foundation (NHF) 2009-2015 pre-commercial research trials (Phase 2) to investigate the viability of setting up a hemp industry in South Africa and to trends and stability of the THC compound levels over different harvests. House of Hemp’s industrial hemp permits allow for the legal handling, possession, cultivating, processing and market testing of cannabis and related products. The following will be the coordinators of the HoH Medical Cannabis Research team:

Team member Envisaged role Dr. Thandeka Ruth Kunene Cannabis Commercial Trials Coordinator. Part of project management team reporting to UFS and liaising with DST and other

stakeholder. Student at UCT Maths Department to develop a Cannabis value chain systems model to evaluate the feasibility and explore community benefit sharing.

Ms. Leanne Blumenthal Coordinating Pharmacological research studies, training and the setting up of the National Medicinal Cannabis Program.

HoH will also bring NHF research partners including the CSIR (Council for Scientific and Industrial Research), ARC (Agricultural Research Council), NAMC (National Agricultural Marketing Council); DAFF (the Department of Agriculture, Forestry and Fisheries) and the IDC (Industrial Development Cooperation) to ensure that the HoH/UFS research activities are aligned with NHF initiative to recommend legislation amendments to allow for the commercialization of industrial and medical cannabis. House of Hemp’s role is to secure permits, collect the cannabis samples; facilitate the securing of funding and the implementation of commercial pilot which will include the substantial participation of emerging farmers in various designated areas of the country where cannabis grows well.

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The proposal University of Free State and House of Hemp propose a “7 year Medical Cannabis Research Study” to investigate medicinal benefits of cannabis; their subsequent applications and the factors related to increasing access of medicines to those who are sick as well as contribute to socio-economic development of rural areas. In considering medical cannabis for South Africa; further research is required on the following: 1. Conduct a meta-analysis of current clinical data and collect and collate all historic and anecdotal evidence re

the use of cannabis in South Africa. 2. Conduct preclinical trial on those that have not been conducted but are important to SA. 3. Conduct clinical trials on those that have done pre-clinical trials but did not have clinical trials. 4. Prove the international clinical trial results of those that have statistical significant correlations linking

cannabis with particular illness relevant in South African prevalent conditions. 5. Investigate if the results are the same for different routes of administration. 6. Compare results using South African strains of cannabis. 7. Collate data on adverse effects and drug interactions of cannabis for different illnesses in South African

conditions.

Thus, it is imperative that research is undertaken and the results of this research will fill research gaps existing in the global cannabis industry as well as confirm some claims for the South African conditions.

Problem Statement Can scientific research prove the medical benefits of cannabis and assist government decide on how best to amend legislation to ensure that South Africans with a medical need can access quality cannabis, while mitigating perceived and actual risks of legally available cannabis at the same time ensuring that the indigenous communities of South Africa also benefit from the emerging cannabis industry? Critical Issues identified:

In this respect, critical issues that have been identified are: 1. What the traditional/indigenous claims of the use of different strains of cannabis for specific medical

conditions in South Africa? 2. Validity of these claims. 3. What compounds are found in the SA cultivars that are high in THC or CBD different from hemp strains? 4. If there is a DNA/fingerprint profile of the SA strains or varieties. 5. How this compares with patented and commercialized international strains? 6. What would be the best way to standardize SA Cannabis extracts using the extracted compounds to meet

international quality standards? 7. How to use these extracts to create innovative SA medical cannabis products? 8. How to ensure that the Indigenous Communities of Practice also benefit in the cannabis commercialization? 9. Aligning South African Cannabis Industry to be in a position to supply Cannabis internationally according to

international standards via commercial export model. In order for us to integrate the use of Cannabis as a conventional medicine, whose efficacy has to be verified, it will require a series of extended studies. This study aims to contribute towards this.

Research Objectives

The main aim of this study is to conduct commercialization research study towards the development and innovation of medical cannabis by increasing accessibility for sick people and influence the commercialization of cannabis cultivation and processing in South Africa, for improved quality of life and sustainable livelihood.

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The (DST) Department of Science and Technology has approved the following as Objectives and related Research Development Innovation (RDI) activities: Objective 1: Indigenous knowledge based concept or Idea generation to identify local claims and innovative

use of medical cannabis which will be compared to the global claims and global market opportunities. Objective 2: Holistic research for discovery of existing local cannabis strains and chemical components;

simple cost effective extraction methods; pre-clinical safety and efficacy studies and related full clinical trials based on positive pre-clinical results.

Objective 3: Applied / Inclusive Innovation using scientific and traditional systems to develop new health technologies, product prototypes as directed by industry based market indications towards commercialization of Cannabis products. Inclusive innovation will include identifying opportunities of shared research with other local and global research institutions as well as the development, testing and optimizing of design and institutional arrangements for implementing a National Medical Cannabis Research Institute (NMCRI) or program within South Africa.

Objective 4: Grass-Roots-Based Technology Transfer by Identifying international partners to assist with the technology transfer throughout the value chain as well as developing relevant and appropriate technologies for local industry applications.

Objective 5: Local cannabis cultivating and Agro-Processing commercial pilot run by a Private Public and Community Partnership (PPCP) in select organized communities in identified provinces. The successful pilot will be rolled out to other IKH (Indigenous Knowledge Holders) communities in all the 9 provinces of S.A.

Objective 6: Marketing pilot to creating awareness on economic opportunities, observe market receipt and map the socio-economic impact embedded in the cannabis industry.

Objective 7: Ubuntu-based models of commercialization to ensure community based and owned enterprises explore embed commercial opportunities of Cannabis and its by-products.

Objective 8: Benefit Sharing models for establishing a national cannabis empowerment trust for participating indigenous communities.

Objective 9: Human Capacity Building, training and skills development of students, technicians, community members, farmers and entrepreneurs throughout this project and along the medical cannabis value chain.

The envisaged outcomes of this study are: Clarity on what Methods and techniques of cultivating, harvesting extracting and processing to be in line with World Health

Organization (WHO) including Good Agricultural Practices (GAP) and other international quality standards. Practical technical procedures for controlling the quality of finished Cannabis products. Introduction of cannabis into clinical environments in order to facilitate disease related clinical trials. Facilitated access of Cannabis to the patients. Regulated cannabis cultivation and manufacturing industries that have strategic competitive advantages in

the global markets. Technology and skills transferred. Activities to be undertaken

In the pursuit of the above-mentioned objectives, the following activities will be undertaken in this study: Activity 1: Literature Research The aim of this activity is to give quality and statistically significant research first based on a desk research towards background and international benchmarking. This activity contributes to objective 1.

Activity 2: Geographic indicators research This activity will do field research to identify where cannabis grows in South Africa and collect samples of indigenous South African cannabis for analysis. During the field trips the researchers will also identify indigenous

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uses of cannabis in South Africa. This activity will result in a geographic and trade map indicators to indicate where, how much and type of Cannabis is grown and what Cannabis is used. Activity 3: Seed breeding pilot This activity will develop better performing high THC and high CDB cultivars and compare seed performance, cost and availability of imported seed with the potential local supply. Activity 4: Cultivating Pilot The aim of this activity is to optimize Cannabis farming models (indoor, outdoor open and rural area hoop houses) and record cultivation factors (Yields: stalks/seed/leaves; Inputs: soil testing/preparation, water, seed, fertilizer, labour, maintenance; Occurrences: diseases, pests). 7 groups of local cannabis cultivation factors and samples will be collected from the 2 sites and analyzed and compared to international yields on Cannabis cultivation including:

1. Existing Lusikisiki Cannabis plants collected from existing “illegal” cannabis plantations. 2. Cultivation Pilot - Open field and hoop houses - using local seed 3. Cultivation pilot – rural areas hoop houses - using local seed 4. Cultivation Pilot - Open field and hoop houses - using world best seed 5. Cultivation pilot – rural areas hoop houses - using world best seed 6. Cultivation Pilot - Controlled environment - Green House in Durban- using local seed 7. Cultivation Pilot - Controlled environment - Green House in Durban - using world best

Activity 5: Pharmacology compounds Limited literature search indicates that Cannabis plants is known to contain at least 489 distinct compounds distributed among 18 different chemical classes, and harbor more than 70 different phytocannabinoids including nitrogenous compounds (27 known), amino acids (18), proteins (3), glycoproteins (6), enzymes (2), sugars and related compounds (34), hydrocarbons (50), simple alcohols (7), aldehydes (13), ketones (13), simple acids (21), fatty acids (22), simple esters (12), lactones (1), steroids (11), terpenes (120), non-cannabinoid phenols (25), flavonoids (21), vitamins (1), pigments (2), and other elements (9). Cannabinoids are the chemical compounds in the Cannabis Plant which imitate naturally produced endo-cannabinoids in the human body; which assist with communication between the cells. The two main cannabinoids are Tetrahydrocannabinol (THC) and Cannabidiol (CBD). Others are Cannabinol (CBN), Cannabicyclol (CBL), Cannabichromene (CBC), and Cannabigerol (CBG) and Tetrahydrocannabivarin (THCV), Cannabitriol (CBT), Cannabielsoin (CBE) and CBDV (Cannabidivarin (CBDV) that are starting to be studied and their related CBGA, CGCA, CBCA, THCA and CBDA. Research further indicates that the relative abundance of these and other cannabinoids can vary depending on a number of factors such as the Cannabis strain, the soil and climate conditions, and the cultivation techniques indicate that even if Cannabis is cultivated and processed under standardized conditions in order to obtain a consistent product; the content of cannabinoids depends on the type of cannabis. The “entourage effect”, a term coined by Dr. Ethan Russo, who, in 2011, published a paper in the British Journal of Pharmacology describing the synergistic contributions of other compounds in cannabis over the isolated compound pharmacological dosages. The effects of all these chemicals working together and regulating each other will be much different than the effects of any one chemical working alone. In other words, cannabis is made up of thousands of different chemicals that work together to produce some general effect. Change the recipe and you change the effect.

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Limited literature study indicates the following biological activities of cannabis compounds as listed below: Alignment/Compound THC CBD CBG CBN CBC THCv CBGa CGCa CBCa THCa CBDa CBDV Tepenes Releaves pain – analgesic X X X X X Suppresses appetite and helps with weight loss – Anorectic

X

Kills or slows bacterial growth – Anti bacterial, Anti Microbial

X X X X X

Reduces blood sugar levels – anti diabetic

X

Reduces vomiting and nausea – Anti emetic

X X

Reduces seizures and convulsion – Anti epileptic

X X

Treats fungal infection – anti fungal

X

Reduces inflammation – anti inflammatory

X X X X X X X X

Aids sleep – anti insomniac X Reduces risk of artery blockage – anti ischemic

X

Inhibits growth in tumors or cancer cells – anti proliferative

X X X X X X

Treats Psoriasis – anti psoriatic X Tranquilizing – used to treat psychosis – anti psychotic/ anti-anxiety, antiolytic

X X

Suppresses muscle spasm – anti spasmodic

X X X X

Relieves anxiety – anxiolytic X Stimulates appetite – appetite stimulant

X

Promotes bone growth – bone stimulant

X X X X X

Modulate function in the immune system – immune-suppressive and stimulation

X

Reduces contractions in the small intestines – Intestinal anti-prokinetic

X

Protects nervous system degeneration – neuro-protective

X

Vasorelaxant X Anti-oxidant X Anti- malaria X Anti-olytic X Anti neoplastic X Appetite increasing X X

The deliverable of this activity is to identify, understand and characterize all chemical and pharmacological compounds found in cannabis from South Africa and answer the following questions: Chemical fingerprinting to compare chemical content. What form is the chemical found in the plant (monocarboxylic acids or decarboxylated chemical

charecterization) Where is the chemical stored in the plant? Determine stage when it is highly expressed in the plant? The relationship ratio between the raw materials under different conditions. The effects of heat, light, humidity, acidity and oxidation on the stability and possible conversions from one

compound to another due to exposure to different elements (heat, moisture) and or change in colour or aroma.

Identify point of conversion and rate of change between compounds and related stability levels? Stability of the chemicals.

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Point of conversion and or decomposition of chemicals. Comparison of compound and conversion rate in the raw materials versus extracts. Identify the need for product irradiation to ensure that users are not exposed to toxic spores which may

contaminate the plant material including bacterial, fungal, microbes and moisture testing. Determining best/ideal storage conditions (temperature, humidity, light, years) and recommended shelf life. Activity 6: Extraction of compounds

The aim of this activity is to extract raw materials from the harvested Cannabis trees and map processing factors in order to outline the cost benefits of processing trees into primary raw materials. This will include: • Extract THC from leaves and buds. • Extract CBD from leaves and roots. • Extract any other eminent chemicals. • Chemical and concentration component analysis by year. • The relationship ratio between the raw materials. These extracts will be compared as per different strains, geographic area, growth condition, part of the plant, dried or fresh and extraction solvents etc.

This activity will also identify all pharmacodynamics properties linked with the different cannabis compounds found in local cannabis and investigate the following: Phytocannabinoid-Phytocannabinoid Interaction and Phytocannabinoid Differences among strains. Factors affecting the nature of the potential phyto-cannabinoid-phyto-cannabinoid interactions.

Pharmacokinetic vs. Pharmacodynamic interactions. Psychological and physiological effects associated with varying phytocannabinoid concentrations.

Pharmacological actions of other compounds found within cannabis (e.g. terpenes, flavonoids), substantiating

the entourage effect.

Activity 7: Conversion into end products

The aim of this activity is to develop and profile the range of products that can be derived from locally produced cannabis and or cannabis compounds for specific medical applications. The decision on the final medical end products to be produced will be determined after the research study and after activities 1 to 7 which will for have given the study information on local claims and pharmacological profile of the local cannabis. End products to be produced will have the necessary labelling and or insert in final product packaging as per legislative requirements and as per pharmaceutical and package inset requirements in the regulations of the Medicines Act. Each production process recorded must description of process, in process controls, validation of process, characterization, control of impurities and specifications for the following processes:

Documentation Complete batch documentation detailing the entire process Production processes including Quality management System Quality Assurance Functions Quality Control processes including qualitative and quantitative analyses If any additional technical services such as Contract Manufacture, extraction and Analysis Detailed information regarding the Distribution processes. Processes in place for handling Complaints. Complete traceability in the even Recall. Inspection processes to validate suppliers and internal processes. Personnel needed to produce said product, as per skills required for each specific step in the process Specific Premises details and all the equipment that will be needed to produce the said products.

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Quality consideration - The validated analytical test methods and standards related to the determination of contaminants and residues will be adopted and used at currently available accredited MCC laboratories, after extensive technical review from some existing technical documents available internationally. In –line with International Recommended Methods of Laboratory Testing Cannabis, the research study will include the subcontracting MCC accredited labs to conduct the following on end products developed:

Standardize Medical Cannabis Testing for Potency - all flower and processed products, such as edibles and concentrates, are tested for Delta 8 THC, Delta 9 THC, CBD, CBN, CBG and CBC content. This will be done using High Pressure Liquid Chromatography and GEC equipments.

Standardize Medical Cannabis Testing for Pesticides; Herbicide, fungicides and pesticides residue levels will be determined including aflatoxin levels using Mass Spectrometers.

Standardized Chain Reaction Testing for Molds and Mildew using Real-time Polymerasa. Consistency of both the crop and the THC and CBD levels - Quality of any medicinal plant is monitored

throughout all the stages of production from growing, harvesting, storage, preprocessing and all post harvest activities A monograph will be developed to control the quality and consistency. HPLC, LC-MS and DART will be used to set up minimum acceptable limits of all marker compounds.

Edibles - Nutritional content of the plant will be determined and a " Fit for Human Consumption" studies will be done

Toxicity including eco toxicity - Toxicity will be done at all levels of research (environmental impact studies for the cultivation will be done).

This activity will include the development/verification of testing standards and the maintenance of a Cannabis laboratory testing reference library. The product development activities will be undertaken in partnership with existing industrial partners who have existing expertise and equipment to develop specific medical cannabis product prototypes in order to test the market and export opportunities. In addition, this activity will also investigate utilizing modern intermediate scale technologies to support existing downstream SMEs (Small and Medium Enterprises) and to explore further high value add enterprises opportunities in the Cannabis Value Chain. This activity will also include feasibility studies of producing specific products to patients. Activity 9: Clinical Studies

In year two or three, after the preliminary research: cultivation, extraction and conversion into end products this research study will also conduct preclinical and clinical trials using extracts and products developed to verify potential/claimed therapeutic uses to determine the validity of international and local claims to determine effective therapeutic indications of cannabis in particular the 10 diseases identified above that are prevalent in South Africa and were prioritized by the government. The pre-clinical and clinical trials will determine/optimize/verify the following key aspects/factors of using cannabis for medical purposes:

Routes of administration Medical cannabis is used as a medicine taken in a various methods of consumptions. Different methods of consumption have different effects. The study will record, test and verify the different routes of administration for different applications of cannabis including:

Teas (prepared from leaves and flowering tops) Vaporizer (used with extracted oils) Oils

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Tinctures Smoking (Cannabis smoke is harmful?) Edible foods containing cannabis (e.g. butters, oils, brownies, cookies) Oro-mucosal (liquid extracts as sprays); Rectal Topical (ointments, creams, or lotions) Pills and existing cannabis based prescription products. Syqe actuator/inhaler, a first in class pocket sized metered dose cannabis inhaler, poised to become the

most advanced and versatile inhalation-based drug delivery platform of its kind.

Dosage and dosing information

Limited literature search indicates that estimating the correct dosage is difficult to do because: Precise dosages forms or uniform dosing schedules have not been established. Dosing remains highly individualized. Dosing does not fit well with the typical medical model for drug prescribing. Dosing it is affected by the source of the plant material, its processing, and by different routes o

administration. Standardization of extracts in terms of availability of dosage. Dosing relies to a great extent on titration (i.e. finding the right dose where potential therapeutic effects

are maximized while adverse effects are minimized). Dosages with inconsistencies with each harvest e.g. Growing and harvesting of the plants will be

controlled to minimize chemical variations and a monograph will be developed to set minimum acceptable quality levels

Explore if one harvest yields 90% THC and the other yields 70% THC, who decides on the dosage for the patient??? The Phase II clinical trial dose studies will determine the minimum efficacious levels and these will set up the quality standard for efficacy.

The study will collate international research relating to dosage and dosing information and make recommendations in line with the Health authorities internationally. A detailed comparative study of all the dosage allowances approved by these authorities to establish the correct dosage for each specific ailment. Scientific evidence for clinical trials will also assist. Dosage will be based on traditional use and then verified through Phase II dose efficacy studies (Please note that this will be an oral formulation not smoked). The study will also indicate overdose/toxicity issues especially in the cases of long term and intensive use of cannabis and recommend what drugs to administer in case of overdose. These clinical study results will contribute some knowledge around dosage and dosage information to some of the research gaps. The result of this study will prepare and avail information to provide patients and healthcare practitioners with information relating to daily amounts and dosing as per different therapeutic application in the priority illnesses. Dosage Form and Drug Delivery Mechanisms: The limited literature study shows that different drug delivery patterns may be warranted in treatment of different disease conditions. Thus this study will investigate and record drug delivery systems design, formulation, development and evaluation. This study will be performed in collaboration with Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand; where extensive studies are being done on Drug Delivery Platforms towards the development of novel polymeric devices (tablets, capsules, multi-particulates, implants) that may be

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applied in the delivery of a wide range of drugs with different physicochemical and physio mechanical characteristics. The Wits department works closely with the Cancer Research unit of the university. Pharmacokinetic properties

This study will determine the pharmacokinetic properties of the cannabis and the compounds analyzed and extracted. Pharmacokinetic properties to be investigated will be in line with the ADME principles and those that were identified in the limited literature search including:

Absorption, solubility, bio-availability and variability of cannabis and its constituency into the body. Distribution and distribution volume of cannabis constituency through-out out the body after absorption. Presence and the concentration of cannabinoids in tissues such as blood supply; heart, brains, lungs, liver

and kidneys and fatty tissue Elimination and excretion (through the feces; urine; sweat; how long it stays in the body) Metabolism involves allylic oxidation, epoxidation, decarboxylation, and conjugation.

Linked with pharmacokinetic properties, this study will record tolerance, dependence, and withdrawal symptoms as follows:

Tolerance state of adaptation in which exposure to the drug causes changes that result in a diminution of one or more of the drug‘s effects over time.

Dependence can be physical dependence and psychological dependence (i.e. addiction vs habit forming). Withdrawal symptoms when use is abruptly halted or discontinued. Determining pharmacokinetic-pharmacodynamic relationships. Reversibility of effects. Cannabis dependence and cannabis excess.

Pharmacology of the linkages of other compounds found in cannabis

The pre-clinical and clinical trials will attempt to allocate each compound with alignment. The study will test local claims that will be unveiled during the national field trips as well as international claims from literature study. Finally the study will try to unveil more about the pharmacological actions of the various other compounds found within cannabis (e.g. terpenes, flavonoids). Literature search indicates that some of these compounds (e.g. terpenes) may have a broad spectrum of action (e.g. anti-oxidant, anti-anxiety, anti-inflammatory, anti-bacterial, anti-neoplastic, anti-malarial), but this information comes from a few in vitro and in vivo studies and no clinical trials exist to support these claims. Contra-indications and warnings

One of the attractions to Cannabis is claims that current registered western medicines have too many side-effects; at the same time there are many studies that list many contra-indications of using cannabis and some have claimed that side effects associated with the use of cannabinoids limit their therapeutic utility. PLEASE note: that these side effects can also be related to the incorrect dose or dosage forms or concentration of THC/CBD, it is therefore imperative that sufficient studies are done to ascertain all these uncertainties.

The resulting research study report will include a collation of international and local research on contra-indications or any other significant adverse effects and warnings as experienced by patients and doctors during clinical trials as per the prescribed legislative requirements and make recommendations in-line with the Health authorities internationally.

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Interactions with other drugs The study will collate international research relating to interaction with other drugs for identified priority ailments and make recommendations in line with the Health authorities internationally. Some identified in limited literature search are listed below: Cannabinoid–mediated regulation of drug metabolism and drug transport Drugs that increase the bioavailability of cannabis and with that, possibility of additional side-effects. Drugs that accelerate the breakdown of cannabis. Cannabis decreases the dosage required by other drugs. Cannabis increases the dosage required for other drugs to be effective. Interactions are also possible with drugs which (like dronabinol) are strongly bound to plasma proteins.

Monitoring The final task of the clinical trials will be to monitor all these activities and from data and scientific analysis; develop clinical guidelines on monitoring patients who are taking cannabis for medical purposes and initiate an appropriate pharmacovigilance plan in place to monitor the patients appropriately and in this way conduct ongoing pharmacovigilance evaluation. Clinical trial protocols Six months before the envisaged start of Clinical trials the protocol for clinical trials and related controls will be written and submitted to MCC for clinical trials that will determine safety and efficacy of cannabanoids and cannabis based medications and compounds in identified priority diseases. Protocol will include the following: Sampling for control and volunteer cohorts to include sample size and statistical significance factors as well as

selection, treatment and exclusion criteria of subjects. Study design. Assessment of efficacy and safety with various potency. Toxicology - Safety and toxicology studies including

Phase I clinical studies will be done to determine safety and toxicology studies (pesticide, herbicide, heavy metal and microbial content studies all will form part of the safety and toxicology evaluation of the studies) Efficacy will also be determine through laboratory studies (Preclinical work and Clinical studies - Phase II clinical trials to Phase III studies).

Other adverse effects and other contraindications. Investigators. Statistics Quality control and assurance. Ethics Data handling and record keeping Publication policy Project time and table flow chart with clear indications of phase 1, phase 2 and phase 3. Activity 9: Marketing

The aim of this activity is use the harvest and products developed from the medical cannabis trials to conduct market research to identify market opportunities, test market for specific products, estimate demand and growth potential for the specific markets (local and export) as well as track market response to South African cannabis and cannabis based products. This will include:

• Market research • Market testing. • Marketing and penetration strategy. • Marketing extracted chemicals. • Distribution local and international. • Marketing end products.

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• Educative and awareness raising. • Feedback from market in terms of product use.

Activity 10: National Medical Cannabis Access Program

The aim of this activity is to develop and implement the ‘National Medical Cannabis Access Program (NMCAP) for access to Medicinal Cannabis’ to ensure that seriously ill citizens have the right to obtain and use cannabis for medical purposes where that medical use is deemed appropriate and has been recommended by an accredited physician who has determined that the person’s health would benefit from the use of Cannabis. This NMCAP program must be sustainable and viable within an appropriate regulatory framework and institutional arrangements possibly under the auspices of the National Hemp and Cannabis Foundation.

This NMCAP activity will also explore best models to ensure access to the patients and will assist by describing procedures for dispensing cannabis, including:

A ‘pre-approved’ list of diseases wherein the use of Cannabis is approved. A register of accredited prescribers. Refer to legislation to ensure such a definition is in line. a register of all qualified patients - nationwide identification card system A register of all accredited dispensers. An accredited medical cannabis course. A designated provider especially during the research when the cannabis medicine is still unregistered.

In addition, to ensure that qualified patients and their primary caregivers who obtain and use Cannabis for medical purposes upon the recommendation of a physician are not subject to criminal prosecution or sanction.

This activity will also recommend the following Access Regulations and policies are in place Application process is user-friendly and equitable. Appropriate Cannabis Licensing Authority which could be a subcommittee of the MCC and will also look at

registration of cannabis based medicines. Control mechanisms. Equitable access to factors of production. Expert advisory committee Good production practices. Institutional arrangements Quality assurance processes. Sample of how the medical permit should be. Security measures Supporting IT program to assist with monitoring and reporting

This activity will also ensure skills transfer to capacitate emerging farmers and SMEs to include: Training of the farmers in business management of cannabis farming. Train and Empower farmers to be fully integrated into the exchange economy. Train and empower SMEs to be competitive in beneficiation and marketing. Training and accreditation of the doctors, health care workers, pharmacists and traditional healers. Breeding program - how to get our local seed to match or out-perform world best. Further value add towards total beneficiation of the cannabis plant along the value chain (waste and seed). Multiplication strategy to other Cannabis growing areas. Setting up of an analytic lab to service the industry.

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In-order not to re-invent the wheel, this program will seek the support of international doctors and professors with specialties in this field, from the Cannabis R&D Institutes Internationally. SECTION 4: PERMITS NEEDED The applicants are asking the department of Health for 8 permits that will allow researchers from UFS and HoH and farm managers from the pilot sites (Lusikisiki and Dube Port) to coordinate and implement the following activities with Cannabis:

Importing seed and tissue culture Breeding local high CBD and high THC cultivars Cultivation and harvesting (with hectrage in accordance and in response to market needs). Packaging Extraction of CBD and THC and other cannabis compounds Testing of chemical compounds Product development and manufacturing Product sales and distribution (including monitoring of post marketing surveillance to determine how the

product performs in the market and how it is received) Exporting (and observance of factors influencing the export market) Product transporting Handling Storage Purchase, acquire, keep, possess, use, supply or sell; Furnish information and advice; Apply for registration of medicine; Formulate for the purposes of registration; Distribute; Repackage of medicine in accordance with the Medicines Act; Initiate and conduct pharmaceutical research and development; and Conduct any other health service as may be approved by council from time to time.

DETAILS OF THE PROPOSED PROCESSES Operational plan Annually the study will follow the operational plan that was developed in the first phase of the National Hemp Foundation as listed below:

- Environmental assessment of identified sites. - Apply for cannabis permit (site & import of seed) - Secure seed - Workshop for farmers (terms of reference for team cannabis, ARC work-plan, roles, good practices) - Collect cannabis seed deliver at pilot sites - Soil preparation, fertilization, planting - Observe germination, supplementary planting or thinning. - Fertilizer after planting – topdressing. (Compare chemical with organic). - Observe insects, pests and diseases. - Crop maintenance. - Prepare for harvest and harvesting. - Drying of buds - Drying and cleaning of seed. - Extraction. - Samples taken for THC and CBD analysis at UFS or any accredited laboratory

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- Cleaning the plots, management and security. - Product development. - Processing into saleable products. - Certificate of analysis - Prepare for exporting to comply with international standards. - Market test and research. - Final report and annual compliance. - Proposal for next season. - 7 year reconciliation and final report.

Cultivar names The study will be Cannabis Cultivars. The study will cultivate and compare local and the international top performing cultivars that are known to be high in CBD and high in THC.

International strains Hemp based with moderate CBD

International strains High CBD

International strains High THC

Local strains (unknown level of CBD and THC

Cultivar Amounts secured Cultivar Amounts secured Cultivar

Amounts secured Cultivar

Amounts secured

Cannatonic 50kg ACDC 10kg White widow - Cannada 10kg Pondoland 1 10kg

Felina 50kg Avidekial 10kg Cush – USA

10kg Pondoland 2 10kg

Future Santika 50kg Raphael 10kg Cheese – Dutch 10kg Durban Poison 10kg

US031 50kg Royal Medic 10kg Israeli 1

10kg KZN 2 10kg

SA HEMP 1 50kg Euphoria 10kg Israeli 2

Limpopo 1 10kg

SA HEMP 2 50kg Compassion 10kg Afghanistan

10kg Swazi Gold 1 10kg

China Hemp 1 50kg Sour Tsunami 10kg Mexico Gold

10kg Swazi 2 10kg

China hemp 2 50kg Cannatonic 10kg Cameroon

10kg Sotho 1 10kg

Australia Hemp 1 50kg Valentine 10kg Jamaica

10kg Malawi Gold

10kg

Australia hemp 2 50kg Charlotte Web 10kg India 10kg Malawi 2

10kg

Kompolti 50kg Hindu Kush 10kg Australia 10kg Mozambique 1

10kg

In the first year, each site will cultivate 25 different cultivar (14 imported and 7 local). As the research study years progress the cultivation trials will decrease number of cultivars to the ones that adapt better in South Africa in terms of phytochemical profile. Area expected to be planted

In the first year, the medical research trial will cultivate a maximum of 4 hectars in 2 sites; ensuring that each site does not cultivate more than the allocated 2ha with a roll out plan in future years depending on the success of the commercial trials, to be extended to one site per province in all SA provinces.

In the first year, the only two sites will be in Lusikisiki Eastern Cape and in Dube Port Durban, kwaZulu Natal. The following table list all the sites that are to be cultivated (pictures of site, permission to occupy site or title deed, GPS coordinates and maps have been supplied). The Lusikisiki site has been designated for cultivation only cannabis. Only the Dube port has been designated to also extract the Cannabis oil. All these sites are not residential dwelling places. There will be no other cannabis trials within 20km radius of these sites.

District / Municipality City Type of facility Address GPS coordinates Ethekwini Durban House of Hemp Agro-

processing facility Dube Trading Port, Greenhouse D, Harvest Avenue, La Mercy, 4399

S 19,60 36 302; E 31.09 05 478

Ngquza Lusikisiki Traditional Council Pilot Site Lundini Great Place, Mantlaneni AA, Lusikisi

S231,16 11.43; E29,22 19.78

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The Eastern Cape Sites is championed by the Department of Trade and Industry to demonstrate how IKS communities can be involved in the emerging medical cannabis industry. The land is owned by the community traditional council who has appointed a local steering committee to coordinate this research study in their land. The Amantlane Traditional Council under the Mpondo Kingdom has agreed to investigate being part of a national cannabis farmer association. This site will be run by an experience indigenous knowledge holder farmer and the Prince of the eMantlaneni (Pondoland) supported by local medical doctors and traditional healers. The KwaZulu-Natal site is a House of Hemp site where House of Hemp has a 5 year lease from Durban Dube port owned by the eThekwini municipality that has allowed House of Hemp to use this state of the art indoor plant to conduct indoor part of the research study. Thus, facility will be run by a professional horticulturalist and coordinated by an experienced pharmacist and supported by a medical doctor.

All farmers, site managers and coordinators to be part of the 2016-2020 trials will undergo cannabis farmers preparation workshop where all site managers will be trained on the complying with regulation and on the code of conduct around the permits in a central venue by the ARC. Once successful this program will be extended to other provinces; with sites to be identified.

Materials to be harvested, transported and stored The cultivation trial will include seed being planted for chemical extraction (CBD and THC); oil processing and for fibre extraction. Harvest will be done such that cultivated cannabis plants and parts thereof will be removed, processed or destroyed after data collection as follows: Seed will be transported from the Durban Port to the ARC where it will be stored until the sites are ready for

planting. Some of the seed harvested will be weighed and sent to ARC-IIC for breeding research purposes. The rest of seed harvested from the sites will be cleaned, weighed and transported to House of Hemp (Riversand) to be pressed into oil. So while waiting for pressing the seed will be stored at House of Hemp warehouse.

Some of the leaves will be transported to UFS to be analyzed and to the CSIR for product development. The rest will be transported to join harvest from Dube Port for commercial research around commercial extraction of the chemicals. Irrecoverable leaves (especially on the outdoor Lusikisiki pilot); will be destroyed by incorporating them in the soil. While waiting for transport the leaves/buds will be stored in a secured warehouse in Lusikisiki. Some of these leaves at Lusikisiki will be used in testing the developed small scale farm gate extraction technology. All the leaves and buds will be stored at Dube Port while waiting for processing.

Samples of leaves, buds and seeds will be taken to UFS and Bio-Industrial and the SAPS for the forensic to test the THC/CBD levels on the cultivars and all matters around the narcotic nature of Cannabis. The UFS or the BioIndustrial lab will store the samples for THC/CBD testing and destroy them after.

Stalks will be taken to the CSIR (PE), House of Hemp (Meyerton) and to the IDC owned SFS (Winterton) for fibre analysis, extraction and fibre based product development. The CSIR or the SFS or HoH will store all stalks received and fibre, hurds, tow processed.

Volunteer cannabis plants to be destroyed before succession planting. All end products produced will be stored at the House of Hemp sites either in Gauteng or in Dube Port. All

products produced will be recorded and pictured with stock list kept and samples preserved for exhibitions/market testing.

Storage will be controlled and monitored. The extension officers will assist sites with site storage of all seed, leaves and buds and stalks until transport is ready to be collected to be taken to the UFS, ARC, HoH, CSIR, or Dube Port.

All team members have agreed to keep good records of inventory levels and movements of seed and stalks for audit purposes for up to five years from date of last permit issued.

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Security Measures The Lusikisiki site will set up a physical barrier in the targeted area to ensure that it is properly secured by fencing of at least 2m height with some razor wire or electrical wire on top that surrounds the whole site. In the four sides of the fence there will be signs stating that it is private property or a restricted area and that unauthorized access is prohibited are appropriate. The area will be locked all times and access will be strictly controlled by the site manager in charge and the supporting extension officer. The local king and traditional council have undertaken to secure the site against potential thieves.

The Dube Port site is well secured within the Dube Agro Port that has 24hr House of Hemp Agro-processing facility in Dube Port is well secured: The HoH warehouse is located in a secure area on the South West of the Durban International Airport at the Dube Port along the R102 on the north of which is Tongaat and Verulam on the South. There is a secure perimetre fence along the area marked C and also along areas marked A and B. There is also access control which regulates access to the entire precinct. The HoH warehouse is located towards the end of the precinct adjecent to empty plots along area A and B. The interior of the warehouse is in a secured section (fenced) and would include control at the access point (locks) at the time of inspection. There is security at the access control and there are CCTV cameras there monitoring the perimetre fensing. CCTV coverage along the greenhouse is monitored within the warehouse. The security conducts patrols of the whole agro-processing centre.

HoH extraction facility in Dube Port

HoH facility in Dube Port is fenced around

Building is surrounded by 2m fence with spikes

Leaves are stored in a lockable room

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The area as it is, is secure and the following additional security measures will be implemented to help protect operations against possible threats, especially as this facility will act as the processing incubator in the first years: PERSONNEL MANAGEMENT Security briefing A security briefing should be conducted regulalry for staff and management. Afterall, security management is only effective with the

participation and cooperation of all staff. Staff will is also best to spot potential anomalies in their working environment that may result in security breaches.

Staff identification All staff members should be documented (IDs and physical address) and issued with nametags or some form of identity which they must wear at all times for easy identification.

Staff entrance There should be a single staff entrance and exit and all a record of movements in and out the building should be monitored. Visitors All visitors must be go through a single entrance where they will be processed and searched. There should also be procedures for

deliveries and contractors. Vetting Staff handling sensitive materials and/or processes should avail themselves for periodic security vetting. OUTSIDE PERIMETER CONTROL Controls Controls and protective barriers for entrance into restricted and administrative areas. The gate could be manned by securitity guards

and they can control access for both vehicles and staff. External restricted areas should be marked clearly Guards

There should also be a guard placed at the main staff and visitor entrance and all workers and visitors must be tagged or should sign in and out. Guards will have radio link.

Company vehicles Company vehicles (especialy those ferrying important goods) should be tracked remotely so that their whereabouts are monitored.

Access Control Access to each area within a site where cannabis is present will be restricted to persons whose presence in the area is required by their work responsibilities. A record will be made of the identity of every person entering or exiting those areas. The system to be installed will be capable of identifying each individual who enters or leaves restricted areas to comply with regulatory requirements and includes requirement of a PIN and an identification card, or biometrics.

Cameras and CCTV Constant Visual monitoring of the perimeter of site, where cannabis is present will be achieved using closed circuit video equipment (CCTVs) to assist in the detection, classification, assessment, and recognition of the images recorded to detect attempted or actual unauthorized access or illicit conduct. Additonal cameras to also view the interior. The visual recording system will be monitored at all times by personnel who must determine the appropriate steps to be taken in response to the detection of any occurrence [of attempted or actual unauthorized access]. If any such occurrence is detected, the personnel must make a record of: the date, time of the occurrence; and the measures taken in response to it and the date and time when they were taken. Keeping all cameras recording 24/7, and having appropriate back-up mechanisms in place be retained for two years.

Intrusion detection system

A 24hr alarm system linked with intrusion detection temper proof beams and intelligent cameras is to be installed. A response plan will be designed to ensure quick action when tampering occurs and detection has occurred. When there are no responsible personnel present, a link to a monitoring station will enable notification to the appropriate personnel and law enforcement.

Access to security systems CCTV and alarms

Steps will be taken to ensure the appropriate control of codes, keys, combinations and other elements of the security system. Only senior personnel including the senior person in charge, the responsible person in charge and any alternate responsible persons in charge should have access to alarm codes, vault combinations and other security elements for the site. Changing combinations and codes on a regular basis and when there are any changes with any senior personnel will assist in ensuring appropriate control of the security system.

Power Supply

In order to comply with regulations, the site security system will operate on a continuous basis and all its components (e.g., sensors, control units and communicators/enunciators, volumetric sensors, glass-break detectors, beam-break sensors) will be supported by an uninterruptible power supply sufficient for 24/7 continuous operation and effective maintenance of the integrity of the security system.

Signage Access to areas within a site where cannabis is present will include signage warning against any unauthorized entry and trespassing. Entrances, Doors and Frames

Doors are fire rated and are equipped with the appropriate locking hardware, door closers, contact switches, and electronic access control mechanisms, to assist in providing appropriate security against unauthorized access. All entranceways will be kept closed and locked to the extent possible given your business operations can assist in ensuring that your site and areas within a site where cannabis is present are secure.

Wall Construction

The walls of the site are constructed to assist in ensuring that unauthorized access to site and areas within site where cannabis is present is prevented. For example, slab-to-slab construction and steel mesh sheets attached to the underside of structural joists assist in ensuring wall security.

Glazing panels Appropriate use of glazing panels assists in ensuring that unauthorized access to site is prevented. For example, any glazing panels used in roofing (in a greenhouse for example) are attached directly to the roof structure in such a manner as to preventing removal from the outside. Building security can be further ensured by using appropriate electronic equipment to monitor glazing elements, including sensors that can detect breakage of glazing panels.

INTERIOR CONTROL

Air filters All areas within a site will be equipped with a system that filters air to prevent the escape of odors and, if present, pollen. A high-efficiency particle air filter is fitted to ensure appropriate ventilation and filtration of exhaust air.

Internal signage Internal restricted areas should be marked clearly (signage) and all staff should know these areas as part of their employment orientation

Sprinkler systems The area controling sprinker system, chemicals, fertilizer and temperature etc. should be restricted and locked by supervisor. MATERIAL CONTROL Incoming For incoming strategic materials, requirements for admission of material and supplies will be established. Materials will be searched and

inspected for possible sabotage. There should also be special controls on delivery of supplies or personal shipments in restricted areas. Outgoing Outgoing strategic material should be documented and controlled.

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Notification of local security officials

For both sites, prior to submitting an application; the applicants provided a written notice to local authorities to inform them of their intention to submit an application. The notice included the applicant’s name, the activities for which the licenses is sought (i.e. that activities are to be conducted in respect of cannabis), the site address (and of each building on the site, if applicable) at which the applicant proposes to conduct those activities, as well as the date when the application will be submitted to Department of Health South Africa.

In the application the names, title and address of the senior official for each of the following local authorities, as well as the date when the notification was provided:

Local police force responsible for providing policing services to the location area of the proposed site; Local fire authority of that area; and Local government (municipality) of that area. Local traditional council in that area. Local agricultural support and extension in that area

Prior the planting the project managers will notify the local SAPS within the area of jurisdiction. Transportation will only be done by the permit bearing program coordinators and the site managers only. Prior to transporting any of the harvested goods and or seeds for cultivation, local SAPS in place of departure and in place of arrival will be notified. Security Tracking System

House of Hemp has acquired the rights to use the internationally acclaimed BioTrackTHC Cannabis tracking system with the following security and reporting features:

BioTrackTHC system harbors the technology required to abide with regulatory standard, ensure security and prevent theft. It comes equipped with multiple features to ensure security, theft protection and compliance diversions and includes the following abilities: - The entire logistics process is tracked, permitting the surveillance of every order from door to door. - The transporter establishes a set route that can be viewed by authorized users. - Plant transactions/movements are continuously monitored with an employee PIN/biometric finger scan. - Only predefined employees who are registered in the system will have access to the System. - The feature ensures that only specific employees are granted access for receiving new inventory. - Traceability System provides reports for all inventory adjustments.

The state can use this system as a portal to receive direct access to all reports in real-time, i.e. all the events, Reports, log cannabis destruction events, pending harvest events, transportation events, existing Inventory Reports log inventory, quarantined inventory and plant count. Analysis and Record Keeping

Both sites will be planted with the same material and compared to each other in terms input factors (seed, fertilizer, water, labour, light), success factors (soil test, soil preparation, maintenance, diseases, external factors), cultivation yields (seed, leaves, buds and roots) and primary processing outputs (THC and CBD oils).

Furthermore all sites will collect data to estimate other internal costs, value chain processes and time it takes to complete each process and to deal with external factors.

Methods of record keeping to be implemented include the following: A detailed description of the proposed record keeping methods and description of the process that will be

used for recording transactions relating to licensed activities, including maintaining appropriate records of transactions and dealings with both suppliers and clients.

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The method of record keeping proposed is permit compliance with the government requirements and allows for the reconciliation of orders for cannabis and shipments and inventories of cannabis.

House of Hemp has a license to the renowned TLV enterprise resource planning software which is effectively an ERP system for commercial Cannabis companies/government bodies internationally that allows for the Medical Cannabis Research team to control and monitor and meet or exceed all government standard reporting requirements. It has ability to give monthly reports on just one click.

Reporting All the activities around this trial will be recorded and records kept for seven years in the offices of UFS and House of Hemp. UFS and HoH will submit an annual report which will include: a. An overall outline of the cannabis travelling along the entire supply value chain from farming, through

processing to the private sector enterprises that take cannabis THC and CBD chemicals to produce samples for identified markets.

b. Identified key critical factors affecting the successful commercializing of cannabis in South Africa including: - Farming Inputs (cultivar obtained, fertilizer, water, labour, costs, leftover seeds) - Farming Yields (seed, leaves, roots) - Farming Income (selling price, off-take contracts, demand, projected revenues). - Inputs for primary processing plus yields (THC, CBD) - Processing income (Selling price, off-take contracts, demand, projected revenues)

c. Analysis including: - Comparison of how the indoor compares with outdoor per cultivar. - Cost benefit analysis. - Data of production and security processes and systems needed. - Direct and Supporting infrastructure needed - Potential challenges and threats. - Impact mapping of potential contribution to economic transformation, poverty alleviation and the

betterment of the lives of many. d. Recommendations on research programme improvements, highlights, challenges, security measures and

institutional to best explore opportunities especially with regards to the operations and management of the cultivation and processing activities.

Reports will include data from the TLV ERP system and the BioTracTHC systems as well as monitoring and recordkeeping data from the implementing team. This will be summarized into an annual report circulated to the DST and all key government stakeholders including the Department of Trade and Industry; the Department of Health, the Department of Environmental Affairs and the SAPS. The UFS and HoH team will give a quarterly update to all the stakeholders in the Quarterly National Hemp and Cannabis Foundation Meeting. The UFS, House of Hemp, site managers, extension officers, staff at ARC, CSIR, NAMC and all subcontracted experts will keep these reports in their offices for inspection at all times. The applicants will willingly meet the

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Department and Minister of Health’s request to provide records, documents and information related with sites and medical cannabis research; in the form and at the time specified by the Minister. SECTION 5: IMPLEMENTING TEAM

The table below lists the Medical Cannabis Research Team: Organization Role Contact person Qualifications Contact details ID numbers University of Free State

Pure Research Coordinator Dr. Motlalepula G. Matsabisa PhD 082 781 9720 6108185646085 Community field researcher Ms. Miranda T. Javu MA 072 467 0755 6801011644080

House of Hemp Holding

Commercial Trails Coordinator Dr. Thandeka R. Kunene PhD 076 448 3757 7103270267086

Pharmacist and GMP Compliance and Training Services

Ms. Leanne Blumenthal B. Pharm 082 600 5445 6409290197083

Eastern Cape site (Run by Lusikisiki TC)

Site manager 1 – head of production Mr. Andrew M. Mdingi Matric, IKS farmer 073 965 9807 5311275769087 Alternative manager site 1 – Quality control Mr. Phumezile Dinwayo BA (Hons) 082 402 7905 7508205734085

KwaZulu-Natal Site (run by CannaMed)

Site manager 2 – head of production Ms. Jeanne Williamson Horticulture Dip 083 703 9397 6804230060088 Alternative manager site 2 – Quality Control Dr. Shinkath Bugwandeen MBCHB 083 458 5748 7102085166087

All the people and partners listed above have agreed to be subjected to a security clearance test and understand that they are operating under the auspices of the National Hemp/Cannabis Foundation. They are willing to be put through strict and rigorous application and review process. The team understands that if they don’t adhere to the conditions of the permits or if they give false or misleading information relating to research, the permits will be immediately cancelled. If the permit gets cancelled it may jeopardizes chances of getting another permit in the next year. Please find ID copies for all team responsible as well as their proof of residence.

The following institutions have agreed to give technical support to the Medical Cannabis research study team: Institution Roles/Responsibility Contact Person Contact

number ARC-ICC Research, Seed storage, Breeding, Dr. Ntjapa Lebaka 014 563 3150 CSIR (Materials) Processing of fibre and product development Dr. Sunshine Blouw 041 508 3244 CSIR (Bio-technology Nutraceutical applications Ms. Tshidi Moroka 012 842 2649

Cosmeceutical applications Dr. Dashney Naidoo 012 841 2926 NAMC Feasibility and marketing studies Mr. Sydwell Lekgau 012 400 9746 DAFF Seed importing permits and feasibility study Mr. Thabo Ramashala 012 319 6358 BioChemical Lab THC Testing and sampling procedure Mr. Rajna Towers 011 822 8135 Industrial Development Corporation (IDC) Commercialisation support Mrs. Unathi Speirs 011 269 3590

In every province the Department of Agriculture has committed to avail researchers, economists and extension offices to support farmers:

Institution Contact Person Contact number Eastern Cape PDA Mr. Sydney Masebeni 040 609 3546 KwaZulu Natal PDA Ms. Thabisile Tsanyane 082 492 4880 Lusikisiki Extension officer Mr. Ndumiso Clearance 083 242 7785 Durban Extension officer Mr. B. Buthelezi 082 953 5259

Furthermore UFS and House of Hemp are working with the following institutions to involve their existing students in the identified research topics: Province University Department Topic Western Cape UCT Mathematics Systems modeling of value chain and impact Eastern Cape Fort Cox Agriculture Optimum cannabis agronomics KwaZulu-Natal Natal Medicine (Anesthesia) Clinical Trials Cohort Gauteng Wits Pharmacy & Pharmacology Faculty of Health Sciences

UFS and HoH will also engage all universities that have some existing Cannabis research programs including University of Fort Hare, University of KwaZulu Natal, University of North West, University of Pretoria, University of Stellenbosch, University of Venda and University of Walter Sisulu. Additionally the applicants have support from international partners with scientific, commercial and technical expertise from Israel, USA, Canada, Jamaica, Netherlands, Australia, India and China.

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All expert consultants to be engaged will also be subject to security clearance. House of Hemp will ensure that the permits will (on expiry) be returned to Department of Health for cancellation with a statement of seed remaining in stock. All sites (Dube Port, Lusikisiki, House of Hemp, UFS, CSIR and ARC) are being prepared for pre-license physical site inspection.

Once the permits are issued the head of research will identify training needs for all team members and participating communities in accordance with task to be undertaken and linked with Activity number 9 (skills transfer).

The Implementing team has demonstrated that it is able to meet all conditions for obtaining for obtaining a research license as outlined in the Medicines Control Act of including all the requisite security clearances have been obtained. The implementing team has also demonstrated that the research program will not result in any risk to public health, safety and security. The applicants believe there are NO grounds for refusing the application for House of Hemp and UFS as they embark on a medical cannabis research study under the auspices of the DST as per the Parliamentary Portfolio committee on Science and Technology’s request towards national imperatives.