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Prepared by Mahmoud M. Abdel-Monem, Ph.D. February 5, 1997 Volume 1: Summary Recommendations *The Summary Recommendations were reviewed and endorsed by Sidney Nelson, Ph.D. and Gary Elmer, Ph.D. from the University of Washington. Introduction In 1996, the Washington Legislature asked Washington State University to explore procedures for a tamper free production of marijuana for use in clinical studies. Mahmoud M. Abdel-Monem, Ph.D., the Dean of the College of Pharmacy, directed a study to examine alternative strategies for securing a legal, safe, and reliable supply for marijuana cigarettes for use in scientific clinical studies. This report contains recommendations for consideration by legislators. In preparing the report, we were guided by several factors including: Marijuana and its main active ingredient THC are classified as Schedule I substances by the Federal government. Until this classification has been changed, physicians prescribing marijuana, pharmacists dispensing marijuana, patients possessing marijuana, and state employees engaged in the growing of marijuana are subject to Federal penalties unless they are engaged in an FDA approved clinical study and licensed by DEA. 2. Marijuana cigarettes for use in FDA approved clinical studies must meet requirements for investigative drugs. This will require that all production be conducted in facilities and be subject to procedures that follow the Guidelines for Good Manufacturing Practices. The product must be subjected to quality assurance and standardization procedures using laboratories that are in compliance with the Guidelines for Good Laboratory Practices. To arrive at the recommendations presented in this report, we examined a large volume of background information, secured the services of a consultant, and contacted several agencies. The summary recommendations were presented to a group of experts and concerned individuals for input. The comments of reviewers are included as an attachment to this report. Recommendations 1. There are no compelling reasons to promote or endorse the use of marijuana cigarettes as an acceptable delivery form of THC for therapeutic purposes. It appears that hundreds or even thousands of patients may benefit if an appropriate delivery form of THC is made available. The needs of these patients must be addressed and efforts must be made to improve their quality of life. However, marijuana cigarettes are not the most appropriate delivery form of THC and the FDA has determined that there is not enough scientifically credible evidence that smoking marijuana is beneficial to permit it to approve the prescription of marijuana for medicinal purposes. The use of marijuana cigarettes as a delivery form of THC has several shortcomings including: a) The amount of drug actually administered by patients is not known. Several factors that are difficult to control, such as patient's smoking technique, will impact the amount of drug the patient receives. b) The exact composition of the substances inhaled by patients smoking marijuana cigarettes is not known. The pyrolysis process changes the chemical composition of the marijuana ingredients and the nature and amount of the various active ingredients in marijuana are difficult to control. c) The costs of production of the marijuana cigarettes are high primarily due to the requirements for a tamper-free operation. As an experimental drug the costs are not likely to be covered by health insurers. This will limit access to the drug. d) Marijuana production operations are subject to diversion and will require diligence in maintaining tamper-free operations. e) The amount of THC in the marijuana cigarettes is much greater than the dose required to produce the pharmacological effects of THC. This significantly increases potential for abuse.
2. The use of cigarettes as a delivery form of THC may have some advantages: a) Smoking is useful for patients suffering from nausea who are unable to retain orally admiru'stered medications. b) Smoking marijuana results in a rapid onset of action of the active ingredients. c) Active ingredients administered by using cigarettes as the delivery form bypass rapid metabolism by liver enzymes (first pass effect). This is one of the disadvantages of oral administration of THC. However, the doses of THC administered are usually great enough to overcome this first-pass effect.
3. An oral delivery form of synthetic THC has accepted medical use and has been classified as a Schedule II drug. It is strongly recommended that efforts be focused on clinical studies of appropriate delivery forms of THC and to expand their use to all patients that may benefit from this drug. Currently, oral delivery is the only approved delivery form of synthetic THC. Other potential delivery forms include gum, sublingual. tablets, lozenges, nasal spray, inhaler, atomizer, and patches. Additionally, a pro-drug of synthetic THC, the THC hemisuccinate, has been investigated in a rectal delivery form. The use of appropriate delivery forms of synthetic THC has several advantages including, a) The amount of drug administered to patients is known and well controlled. b) The nature of the drug administered is known and is not likely to change as a result of the administration process. c) The cost of the drug to patients will be lower than the cost of marijuana cigarettes. It is very likely that the appropriate forms will receive approval by the FDA in a reasonable time and the costs of medication will become covered by medical insurance. d) The potential for diversion of appropriate delivery forms of synthetic THC is much less than that of marijuana cigarettes. e) The potential for abuse of the appropriate delivery forms of THC is lower than that of marijuana cigarettes. If the primary recommendations of this report are not accepted, the following is a set of recommendations regarding the production of marijuana for use in clinical studies. 1. Washington should establish a research program to determine the therapeutic utility of marijuana. Tne program, which must be approved by the FDA and sanctioned by DEA, should have the following characteristics: a) Compare the effectiveness of smoking marijuana cigarettes to other tetrahydrocannabinol (THC) delivery forms, e.g. tablets, suppositories, inhalers. b) Available for a broad spectrum of patients. c) Credible experimental design. d) Well controlled and effectively managed.
2. Washington should explore various strategies to provide patients enrolled in the clinical studies with a reliable and affordable legal supply of standardized THC delivery forms, i.e, marijuana cigarettes, synthetic THC tablets, synthetic THC inhalers, and synthetic THC suppositories.
3. The production of a legal and reliable supply of standardized marijuana cigarettes will require securing DEA approved facilities for: a) Growing the marijuana plants. b) Drying the marijuana plants. c) Manufacturing marijuana cigarettes. d) Storage of new marijuana and marijuana cigarettes. e) Chemical and microscopic analysis of marijuana and marijuana cigarettes. f) Distribution of marijuana cigarettes to patients enrolled in clinical studies.
4. Marijuana may be obtained from one of the following sources: a) NIDA facilities. b) State created facilities in Washington. c) Seized marijuana from illegal traffic. d) Imported marijuana from a foreign country.
5. Obtaining marijuana cigarettes from NIDA facilities is a cost-effective strategy for providing patients with a safe and standardized supply. This strategy will not require a significant expenditure for establishing the facility. Costs will depend on the amount of marijuana needed. Initially, small amounts of marijuana are likely to be needed for limited clinical studies and the costs to the State would be minimal. If the needs increase, the costs will increase proportionally. It is reported that NIDA has rejected requests for supply from researchers who had FDA approved IND and DEA authorization presumably because the proposed research did not meet NIDA goals. It will be necessary that Washington develop a strategy to persuade NIDA to provide a reliable supply of marijuana cigarettes to patients enrolled in clinical studies. This strategy may involve: a) Establish strategic alliances with other states to negotiate with NIDA. b) Seek assistance of states' congressional delegations in persuading NIDA to cooperate. c) Offer to pay NIDA for the costs of production of marijuana cigarettes needed for patients enrolled in the state's clinical research program. d) Washington Legislature pass a non-binding resolution demanding that NIDA supply marijuana cigarettes at actual cost of production for patients enrolled in FDA approved clinical studies. e) Explore the possibility of suing NIDA to force the agency to provide marijuana cigarettes at cost for patients enrolled in FDA approved clinical studies. f) Explore the possibility of contracting directly with the University of Mississippi for supplying marijuana at an estimated maximum cost of $400/Kg and Research Triangle Institute for manufacturing the marijuana cigarettes at an estimated cost of $0.80 per cigarette (in batches of 25,000 cigarettes each). Cooperation between states and coordination of their efforts will increase the chances of success. The cost for preparing the marijuana cigarettes, if demanded by NIDA, is likely to be slightly more than $1.00 per cigarette or approximately $400 per patient month. 6. Washington may choose to establish a marijuana growing operation and cigarette manufacturing operation. The growing operation may take place outdoors or indoors. A preliminary cost analysis is provided in Table 1 based on the production of sufficient marijuana cigarettes to supply 200 patient months assuming 300 cigarettes per month per patient. The advantage of the outdoor operation includes the potential for expansion with a minimum increase in costs of production. The advantages of establishing a state run operation include the state's control over supply and the potential for expanding production to supply other states. The disadvantages include high start-up costs and high recurring costs regardless of the amount of marijuana required for clinical studies and beyond. If initial clinical studies do not support the continued use of marijuana for medical purposes, the State would have a useless facility. 7. Washington may use marijuana seized from illegal traffic for preparation of cigarettes. Although the cost of the crude substance is minimal, the costs of quality assurance of crude material will be high. Also, a facility for preparation of cigarettes must be built. This option is not recommended. It is very difficult to ensure the quality and purity of the seized marijuana Issues of concern include product homogeneity and presence of insecticides or herbicides. 8. Washington may import marijuana from a foreign country. A firm in the Netherlands expressed interest in supplying marijuana for clinical studies in the U.S.A. However, the company was not able to supply a small amount of product to an approved user in the U.S. because of the Dutch government's prohibition on exportation of raw cannabis. Even if the Dutch government's prohibition is lifted, the company has a limited capacity (about 1000 Kg per year) and intends to charge $2,000 per Kg. This option is not recommended because of unreliable supply and high cost. 9. The State should identify the appropriate agency to implement the recommendations in
this report. TABLE I Estimated Costs of Production of Marijuana Cigarettes for 200 Patients Per Year Cultivation
Assumptions:
Estimated Costs of Production of Marijuana Cigarettes for 200 Patients Per Year Outdoor:
Indoor
TABLE 2 Estimated Costs of Production of Marijuana Cigarettes for 10
Patients Per Year
Assumptions:
Growing Operation:
Security:
Glossary of Terms
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