January, 1998
Issue
Since its inception in 1974, NIDA has been the sole administrator of a contract to grow cannabis (marijuana) for research purposes and the only legal source for cannabis in the United States. Scientific studies require a source of cannabis materials that have consistent and predictable potency, are free of contamination, and are available in amounts to support research needs. During the 1970s the demand for cannabis materials was high. As much became known from science about the pharmacology of cannabis and its biomedical and behavioral effects, less cannabis research was done and demand for cannabis materials declined markedly. In the last decade or so the research demand has remained relatively low, such that available supply has exceeded the demand. However, recent State initiatives and an NIH-wide scientific workshop in February 1997 co-sponsored by ten NIH components have generated increased interest in research related to the potential medical uses of cannabis. Thus, there may soon be an increase in requests. Some of these requests will come from NIDA grantees or grantees of other NIH Institutes, which guarantees both a peer and Council review. Others, however, may come from individuals receiving State or private funding and may not have undergone equivalent scientific peer review. As a result of these recent developments, it has become important for NIDA to reevaluate its policies related to the Drug Supply Program, and in particular the growing and supplying of cannabis, to ensure that reviews of all proposals are objective, uniform, rigorous, and appropriate, and are so viewed by the disparate communities of interest. Accordingly, there is a need for Council to develop a set of procedures and guidelines on practical and policy issues related to the-provision of cannabis.
Background
In 1968, the National Institute of Mental Health began funding a Drug Supply Program to provide researchers with compounds necessary to conduct biomedical research. Initially, the program focused on THC and other naturally occurring cannabinoids, and then gradually expanded to a wide range of compounds. (Since its beginning, the program has synthesized or obtained over 1,500 different compounds that have been supplied to over 2,500 researchers.) Cannabis was among the first substances to be made available through the Drug Supply Program for use by scientists conducting both nonhuman research and human research under a variety of investigational new drug protocols. It was grown through a contract with the University of Mississippi. With its establishment in 1974, NIDA became the successor to NIMH as the administrator of the cannabis contract and the sole U.S. source for legal cannabis. NIDA has continued to grow cannabis in order to provide a contamination-free source of cannabis material with consistent and predictable potency for use in biomedical research. Because of international treaty agreements (Single Convention on Narcotic Drugs, 1961) which prohibit entities other than the Federal Government from legally supplying cannabis, NIDA has remained its only legal source. These same treaty agreements as well as DEA regulations require that only the amounts of cannabis needed for medical and research purposes be produced. In addition to the contract with the University of Mississippi, NIDA also supports two contracts with the Research Triangle Institute (RTI) for, among other purposes, the manufacture and distribution of standardized cannabis cigarettes.
NIDA also supplies cannabis to seven patients under single patient so-called "compassionate use" Investigational New Drug Applications (IND). In 1978, as part of a lawsuit settlement by the Department of Health and Human Services, NIDA began supplying cannabis to patients whose physicians applied for and received such an USID from the FDA. In 1992, the Secretary terminated this practice, but decided that NIDA should continue to supply those patients who were receiving cannabis at the time.
Under the current contract with the University of Mississippi for any given year NIDA has the option to grow either 1.5 or 6.5 acres of cannabis, or to not grow any at all, depending on research demand. Generally, 1.5 acres are grown in alternate years. The number of cannabis cigarettes produced from 1.5 acres is about 50,000-60,000, although it can be higher. Cigarettes are produced in three potencies: strength 1 - 3-4 %; strength 2 - 1.8-2.2 %; and strength 3 - placebo, as close to 0% as possible. During the past three years, the following quantities have been shipped: 1994 - 24,000 cigarettes; 1995 - 23, 100 - cigarettes; and 1996 17,700 cigarettes. Virtually all of the cigarettes shipped in the last three years have been for single patient INDs. As of March 1997 there were 278, 100 cigarettes in stock. The cigarettes are maintained in frozen storage and have a useful life of approximately five years.
The contract with the University of Mississippi funds the growing, harvesting and storage of cannabis. It also funds potency monitoring and other services for the DEA. The total contract, including DEA activities, is about $480,000 during growing years and $350,000 during nongrowing years. Of these amounts the costs associated with cannabis are about $362,000 during growing years (for 1.5 acres) and $232,000 during nongrowing years. The remaining $118,000/year (approximately) of the contract is used for DEA activities and is not associated with the growing of cannabis.
There are currently two contracts with RTI. One of these, totaling $615,571/year, funds the manufacture of cannabis cigarettes, as well as the analysis of cannabis material, and the development and production of standardized reconstituted cannabinoid preparations. About 10% of this contract ($61,557/year) is for the manufacture of cannabis cigarettes.
These costs from the contracts with the University of Mississippi and RTI that are associated with the growing of cannabis and the production and shipping of cigarettes are approximately $420,000 during a growing year and $300,000 during a nongrowing year. Funding at this level allows for the production of cannabis cigarettes with a uniform potency and purity, consistency of seed stock, the analysis of THC content and adjustments when necessary, and other activities crucial to the production of research grade cannabis cigarettes.
If it were necessary, NIDA could exercise a contract option with the University of Mississippi to grow an additional five acres at a cost of $310,000. Additional costs would then also be incurred in the RTI contract for the production of the cannabis cigarettes.
The other RTI contract for $1,735,400/year funds the synthesis and analysis of other compounds that are available through NIDA's Drug Supply Program and the purification of other compounds.
NIDA's present policy is to provide cannabis for medical research purposes to either grantees or nongrantees whose research and protocols have scientific merit, providing the research is determined to be an appropriate use of NIDA resources and the principal investigator obtains the necessary licences. For NIDA-funded projects, the project officer reviews the protocol, determines whether the amounts requested are justified and makes recommendations to the NIDA drug supply officer. If the request is from someone who is not a NIDA grantee, the project is reviewed by two outside experts for scientific merit, protocol, and amount of drug requested. Each reviewer then makes a recommendation as to whether or not NIDA should supply the cannabis. If the outside experts differ in their recommendations, a third expert is asked to review the request. In all cases, if cannabis is supplied, there is no cost to the researcher. NIDA absorbs all of the costs associated with the production and shipping of the cannabis, whether it is being provided to a NIDA grantee or a non-NIDA grantee.
In recent years, growing 1.5 acres every other year has been adequate to supply both the seven patients receiving cannabis under individual patient INDs and cannabis research grants. There are indications now, however, that the number of requests may increase, perhaps dramatically. The Division of Research Grants has already reported the submission of three grant applications that deal directly with studying the medical use of cannabis -- one on the short-term effects of cannabinoids in HIV patients, a second on ocular cannabinoid effects, and a third on cannabis in the treatment of acute migraine. In addition, the number of requests from non-NIH applicants also may increase substantially. For example, pursuant to a 1991 law that establishes a Therapeutic Research Program within the Massachusetts State Department of Health and Human Services and a 1996 law that makes it legal for patients in the program to have cannabis in their possession, the Massachusetts Department of Public Health has sought assurances that NIDA will supply cannabis for clinical trials on the plant material as a therapeutic modality. NIDA also has received inquiries from the Executive Director of Special Research Programs at the University of California concerning the provision of cannabis for research purposes. This request is associated with a measure that is currently before the California legislature that would establish a California Medical Cannabis Research Center at the University of California.
An additional consideration relative to the supply of cannabis is the possibility that investigators may request cannabis cigarettes with either a THC potency of greater than 4% or with varying amounts of other cannabinoids. For example, NIDA has received a request for cigarettes with an 8 % potency. Currently, the highest potency manufactured is 4 %. To obtain the higher potency, NIDA would either have to use more crude material or use special, more costly, growing methods.
Current Status
NIDA is evaluating its policies related to the Drug Supply Program, in particular the growing and supplying of cannabis, to ensure consistency and uniformity. The National Advisory Council is being requested to assist NIDA through the development of clear guidelines and policies related to this issue. A subcommittee of the Council has met and determined that the questions listed below should be considered by the full Council. Background and the Council subcommittee recommendations are included for each question.
- Who should administer the contracts associated with the growing and production of cannabis?
Background: According to international treaties, only an agency of the Federal government can produce and supply cannabis. Although NIDA has been the responsible Federal agency since 1974, any other Federal agency could assume both the costs and responsibilities of maintaining the farm and supplying cannabis. NIDA's legal authority allows for the provision of cannabis only for drug abuse research purposes. Nonetheless, as a result of the court settlement noted earlier, in addition to providing cannabis for research activities, NIDA also provides cannabis to the seven patients still covered by the single patient INDs.
Over the past few years, there have been very few requests from NIDA grantees for cannabis cigarettes. As a result of expected increases in the number of requests, however, a consideration in who administers the contracts is the dollar cost and its potential impact on the ability to support other NIDA-funded drug abuse research. Further, there now exists a NIDA standard cannabis cigarette that drug abuse researchers can rely on for consistent potency and quality. If NIDA doesn't maintain the farm, there could be less assurance that these standard cannabis cigarettes will continue to be available to NIDA grantees.
Council Subcommittee Recommendation: The Council subcommittee recommends that NIDA continue to maintain responsibility for the contracts. This would ensure that the quality of the cannabis cigarettes is maintained and that NIDA grantees continue to have a source of cannabis with a uniform consistency.
The subcommittee also recommends that the growing methods be evaluated. The current methods may not be state of the art. Alternative methods, such as hydroponic, may be more efficient. Use of other methods may also make it easier to respond to increases in demand if there is an increase in the number of meritorious requests. The use of newer growing methods would also facilitate the production of varied types and compositions of cannabis cigarettes.
- What mechanism should be used for determining which researchers should receive cannabis?
Background: NIH-funded proposals have been through a rigorous scientific review and have received a priority score based on their merit. NIDA staff can rely on this review to determine whether or not to supply cannabis. Requests from other sources, however, may or may not have been scientifically peer reviewed, and do not have a priority score or indication of feasibility of study design or level of enthusiasm. NIDA policy has been to request two outside evaluations of requests for cannabis that come from outside sources. The reviewers are asked to give a recommendation as to whether or not NIDA should provide cannabis. They do not give the proposal a priority score. It is very likely that the number of requests from non-NIH funded sources will increase markedly and NIDA must be able to clearly justify its decisions. It is therefore important that NIDA evaluate the adequacy of its current review procedures. In doing so, consideration should be given to ensuring that the review procedure is able to handle a large number of requests and to conduct an equivalent review -- one as rigorous and comparable to that conducted by an NIH study section as is possible. Attention also must be paid to the process by which scientific experts are selected, such that members of the review panels have scientific expertise related to the disease states being studied, as well clinical pharmacology and therapeutics.
Council Subcommittee Recommendations: The Council subcommittee agrees that NIDA should not have the sole responsibility for determining who should receive cannabis and that other NIH Institutes with an interest in cannabis research should be involved. The subcommittee also recommends that a clear and uniform procedure be established for determining which researchers should received cannabis. It is recommended that this procedure consist of a two stage review. The first stage would involve a review by the funding agency, either NIH or an outside agency or state or local government. Those applications that are determined to be meritorious at the first level of review would then receive a second stage review. This review would focus on the appropriateness of the request for cannabis. Several options are proposed as to how this second stage should be conducted. The preferred mechanism is to establish a standing review committee composed of representatives, from relevant. NIH Institutes and outside reviewers. The committee would consist of a core group of scientists that is supplemented, as needed, by ad hoc scientific reviewers with expertise related to specific disease states and/or clinical pharmacology and therapeutics. In order to avoid any delays in funding, this review would take place shortly after IRG review, in the case of NIH grants or shortly after the receipt of the request, in the case on non-NIH grants. The Council subcommittee does not feel it is necessary for grants that are not funded by NIDA to come before the NIDA Council. However, NIDA should provide Council with periodic reports on cannabis requests and usage.
- Should cannabis continue to be available to researchers at no cost?
Background: Presently NIDA absorbs all costs associated with the growth, production and shipping of cannabis, regardless of whether or not the request is from a NIDA-funded investigator. Grants related to research on the medical use of cannabis have already been submitted to other NIH Institutes and a request for cannabis from a non-NIH funded investigator has been submitted to NIDA. If the number of requests continues to increase, the cost to NIDA could be substantial. The use of funds to produce cannabis cigarettes for non-drug abuse research purposes represents a diversion of resources intended for drug abuse research.
NIDA also currently provides services such as potency monitoring and paraquat analysis for the DEA through the cannabis production contracts. In addition, the DEA serves as an intermediary for individuals wishing to acquire cannabis for training dogs to sniff drugs. NIDA receives no compensation for these services.
Council Subcommittee Recommendation: The subcommittee emphatically agrees that NIDA should not continue to supply cannabis to researchers free of charge. The following are specific recommendations for several types of requestors:
- DEA -- The subcommittee noted that NIDA's resources are intended to be used for drug abuse related research purposes, but that the DEA activities that are currently funded through NIDA's contract with the University of Mississippi are not research related. The subcommittee therefore recommends that NIDA either receive compensation for DEA activities that are currently funded through the NIDA contracts, or discontinue these activities.
- NIH grantees - The subcommittee recommends that NIH grantees reimburse NIDA for the cost of cannabis that they receive. The subcommittee, however, also expresses concern about the impact on indirect costs and ultimately on the cost to the funding Institutes, should cannabis be included in grant costs. It suggests either that cannabis costs be excluded from indirect costs or that each Institute -- rather than the grantee -- reimburse NIDA for the cost of the cannabis.
- Non-NIH researchers - The subcommittee recommends that non-NIH researchers also be requested to reimburse NIDA for the cost of cannabis, as is possible. The subcommittee recognizes that NIDA will have to determine the availability of an appropriate mechanism for cost recovery from non- Federal entities.
Other Considerations
The subcommittee takes note that NIDA over the years has supported research on the clinical pharmacology of cannabis and recommends that NIDA now consider conducting research on the clinical pharmacology of cannabis at varied potencies and with different cannabinoid mixes. Most clinical studies have been conducted using cannabis cigarettes with a potency of 2-4% THC. However, it is anticipated that there will be requests for cannabis cigarettes with a higher potency or with other mixes of cannabinoids. For example, NIDA has received a request for cigarettes with an 8% potency. The subcommittee notes that very little is known about the clinical pharmacology of this higher potency. Thus, while NIDA research has provided a large body of literature related to the clinical pharmacology of -cannabis, research is still needed to establish the safety of new dosage forms and new formulations. Furthermore, drug interactions with other pharmaceuticals and alcohol have seldom been studied for any of the potencies. The subcommittee feels that it is within NIDA's purview to conduct research to address the clinical pharmacology and safety of cannabis and it recommends that NIDA continue to vigorously conduct this type of research.