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Appendix B ACCESS TO A-9-THC AND MARIJUANA FOR RESEARCH AND TREATMENT The investigational use in human subjects of A-9-THC and marijuana are controlled by the Federal Food, Drug, and Cosmetic Act and the Investigational New Drug Regulations issued under that Act. In addition, A-9-THC and marijuana are controlled under the provisions of the Controlled Substances Act and currently are controlled in Schedule I of the Controlled Substances Act. Schedule I drugs are those that have: (l) high potential for abuse, (2) no currently accepted medical use in treatment in the United States, and (3) lack of accepted safety for use under medical supervision. Basically two agencies work together for enforcing the controls of the Act: the Food and Drug Administration (FDA) in the Department of Health and Human Services and the Drug Enforcement Administration (DEA) in the Department of Justice. The Department of Justice was petitioned to reconsider the rescheduling of A-9-THC and marijuana in l972, but to date there has been no change. However, DEA and FDA are now under court order to reconsider this situation. An FDA advisory meeting, held in June l98l, considered the scheduling status of the A-9-THC capsule only (Federal Register, l98l). The committee recommended that the A-9-THC capsule be changed from Schedule I to Schedule II status when a new drug application for A-9-THC is approved by FDA. Schedule II drugs are those that have: (l) a high potential for abuse, (2) a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions, and (3) abuse that may lead to severe psychological or physical dependence. Complaints and concerns were expressed to the study committee about the supply and distribution of marijuana and A-9-THC for treating chemotherapy side-effects in cancer patients. On the one hand, physicians said that there was poor cooperation from federal agencies engaged in controlling and supplying the drug (Roller, l98l; Monsma, l98l), particularly with respect to (l) potency of A-9-THC received (concentrations were too low to be effective), and (2) uncertainty and irregularity of the shipments of the drug. On the other hand, some clinicians felt that it was premature to release A-9-THC for use in cancer patients (Moertel, l98l; Cook, l98l) because: l7l
l72 * specific indications have not been established, in that the way in which chemotherapeutic agents cause nausea and vomiting is not known; * specific populations of patients have not been established; * effective dose schedules have not been established; * safety of treatment at doses effective for antiemetic purposes remains in question; * reported peer-reviewed experience is contradictory and still fragmentary; and * controlled, randomized, prospective studies have not been conducted. Depending upon the use of the drug, two different agencies are in charge of supplying marijuana cigarettes and A-9-THC capsules; the National Institute on Drug Abuse (NIDA) controls the supply of marijuana cigarettes and/or A-9-THC capsules for basic research, and the National Cancer Institute (NCI) controls the supply of A-9-THC capsules for cancer treatment. The processes of obtaining supplies from each agency (or for each purpose) differ. OBTAINING THE MARIJUANA CIGARETTES* To obtain marijuana cigarettes for basic research,t an investigator must register with DEA (apply for a license), file a Notice of Claimed Investigation Exemption for a New Drug (IND)tt with FDA, and submit an order for drug substance to NIDA. The agencies suggest that all the paperwork be filed concurrently in order not to unnecessarily delay the process. FDA analyzes the scientific protocol and determines if the project has scientific merit, if the researcher is qualified, and if IND requirements are satisfied. DEA sends an agent to supply the order forms, to determine from local police records whether the investigator has a drug trafficking record, and to see if the investigator has provisions for keeping the drug secure from theft. On notification of approval by FDA and DEA, NIDA will supply the drug. The entire process is supposed to take from 30 days to 6 months, including the visit from the DEA (Tocus, l98l). However, some investigators have contended it can take longer. To obtain marijuana cigarettes (or A-9-THC capsules) for investigational treatment of glaucoma, multiple sclerosis, or Concentrations of A-9-THC range between 0.5 and 2.8 percent; the marijuana cigarettes contain other cannabinoids, as well as other chemicals. tDEA and FDA do not fund research. Federal agencies that have supported cannabis research in FY l979 (in order of percent cannabinoid research) are: NIDA (84), NIMH (5), NIAA (3), NCI (2), DOT (2), USDA (2), NEI (l), NICHG and NIGMS (less than l). ttTwelve states hold their own IND as of September l98l.
l73 anorexia, the physician must go through the basic research route. In view of the possible contaminant problems with aspergillus and salmonella, it may be necessary to provide sterilized marijuana cigarettes to patients. OBTAINING THE A-9-THC CAPSULES* As a Schedule I drug, A-9-THC can only be used for investigational purposes. However, some cancer patients undergoing chemotherapy treatment and resistant to standard antiemetic drugs benefit from the antiemetic properties of A-g-THC. Therefore, a system has been established for the distribution of A-9-THC capsules to chemotherapy patients within the guidelines of the Schedule I restrictions. A physician who wants to dispense A-9-THC capsules to his cancer patients does so under NCI Group C distribution system (Group C Guidelines, l980). The physician sends an FDA registration form to a DEA-approved hospital pharmacy. The pharmacy forwards the application to NCI, which holds its own IND. NCI evaluates the credentials of the physician, and, if approving, informs the pharmacy to supply the physician. This process, under emergency situations, can take as little as 24 hours (Abraham, l98l). A physician may also obtain marijuana cigarettes for cancer patients in an NCI-approved treatment program. More than 500 hospitals have been invited to participate (Abraham, l98l), and about 300 have clearance from DEA (Gunby, l98l). Shipments began late last fall (Gunby, l98l). More than l,500 physicians have applied, and l,000 have been approved by DEA (Gunby, l98l). The doses available in capsule form are 2.5 and 5 mg. At least one company has submitted a New Drug Application (NDA) to the FDA for manufacture of a synthetic A-9-THC capsule to treat cancer patients (Federal Register, l98l; Tocus, l98l). If an NDA for A-9-THC is approved, a Schedule I status will no longer be appropriate. In fact, the Drug Abuse Advisory Committeet recommended that the A-9-THC capsule be changed from Schedule I to a Schedule II status when an NDA is approved by FDA. *Purity of A-9-THC capsules is better than 96 percent (97-98 percent, C. Turner, l98l, and l00 percent, D. Abraham, l98l). tThe committee advises the Commissioner of Food and Drugs regarding the scientific and medical evaluation of all information gathered by the Department of Health and Human Services and the Department of Justice with regard to safety, efficacy, and abuse potential of drugs and other substances and recommends action to be taken by the Department of Health and Human Services with regard to the marketing, investigation, and control of such drugs or other substances.
l74 SUPPLIERS OF MARIJUANA CIGARETTES AND A-9-THC CAPSULES Marijuana cigarettes are supplied to NIDA by Research Triangle Institute, which stores and distributes them (Davignon, l98l). Many contractors are engaged in the synthesis, storage, and distribution of A-9-THC capsules to NCI. Manufacture is done by Aerojet Propulsion Labs (large scale) and Arthur D. Little (small scale). Stanford Research Institute assays A-9-THC. Banner Gelatin encapsulates it. Flow Laboratories stores and ships A-9-THC to DBA-approved hospital pharmacies. REFERENCES Abraham, David. Investigational Drug Branch, Health Science Administration, National Cancer Institute, Bethesda, Md. Personal communication, l98l. Cook, D.A. Private practice, Bay City, Mich. Personal communication, l98l. Davignon, Paul. Chier, Pharmaceutical Resources Branch, National Cancer Institute, Bethesda, Md. Personal communication, l98l. Federal Register, Volume 46, Number 3l, February 24, l98l. Study of the health-related effects of marijuana use, pp. l38l6-l38l8, l98l. Group C Guidelines for the use of A-9-Tetrahydrocannabinol NSCl34454 for nausea and vomiting induced by antineoplastic chemotherapy. Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Md., September, l980. Gunby, P. Many cancer patients receiving THC as antiemetic. JAMA 245:l5l5-l5l8, l98l. Roller, C.A. Assistant Professor of Internal Medicine, Division of Hematology and Oncology. University of Michigan, Ann Arbor, Mich. Personal communication, l98l. Moertel, C.G. Director, Mayo Comprehensive Cancer Center; Professor of Oncology, Mayo Medical School; Chairman, Department of Oncology, Mayo Clinic, Rochester, Minn. Personal communication, l98l. Monsma, Stephen V. Senator, State Senate of Michigan, Lansing, Mich. Personal communication, l98l. Tocus, Edward C. Chief, Drug Abuse Staff, Food and Drug Administration, Rockville, Md. Personal communication, l98l. Turner, Carleton. Director, Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, Miss. Personal communication, l98l.