ANNOUNCEMENT OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES' GUIDANCE ON 
PROCEDURES FOR THE PROVISION OF MARIJUANA FOR MEDICAL RESEARCH

Release Date:  May 21, 1999

National Institutes of Health

I.  Introduction

The intent of this document is to provide guidance to the biomedical research 
community who intend to study marijuana in scientifically valid 
investigations and well-controlled clinical trials on the procedures of the 
Department of Health and Human Services (HHS) for providing research-grade 
marijuana to sponsors.(i) 

The production and distribution of marijuana for clinical research, is 
carefully restricted under a number of federal laws and international 
commitments.  The manufacture, acquisition, and distribution of marijuana is 
subject to control under Schedule I of the Controlled Substances Act (CSA) 
(21 U.S.C. 801 et seq.), the most restrictive of the five federally regulated 
classes of controlled substances.  Persons who wish to conduct research using 
Schedule I substances such as marijuana must obtain a special registration 
under the CSA from the Drug Enforcement Administration (21 U.S.C. 823(f)).  
To receive such a registration, a researcher must first be determined by HHS 
to be qualified and competent, and the proposed research must be determined 
by HHS to have merit (id.).  Moreover, persons who intend to study marijuana 
for use in the cure, mitigation, treatment, or prevention of disease are 
subject to the �drug� and �new drug� provisions of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321 et seq.).  

The United States is also a party to the Single Convention on Narcotic Drugs, 
an international narcotics control treaty.  Parties to the Single Convention 
have agreed to limit production, distribution, and possession of cannabis and 
cannabis resins to authorized medical and scientific purposes (Art. 4).  In 
addition to these and other controls, Articles 23 and 28 of the Single 
Convention provide that if a country allows cultivation of the cannabis plant 
for research purposes, the country must establish a national agency to 
control the cultivation and distribution of the crop.  Currently, the 
National Institute on Drug Abuse (NIDA), a component of the National 
Institutes of Health (NIH), oversees the cultivation of research-grade 
marijuana on behalf of the United States government.

An appropriate scientific study of a drug substance requires, among other 
things, that the substance used in the research must have a consistent and 
predictable potency, must be free of contamination, and must be available in 
sufficient amounts to support the needs of the study.  NIDA allocates 
resources to cultivate a grade of marijuana that is suitable for research 
purposes.   Recently, there has been considerable interest in determining, 
through scientifically valid investigations, whether cannabinoids can provide 
positive medical benefits.  In February 1997, an NIH-sponsored workshop 
analyzed available scientific information and concluded that "in order to 
evaluate various hypotheses concerning the potential utility of marijuana in 
various therapeutic areas, more and better studies would be needed."(ii)  Most 
recently, the Institute of Medicine issued a detailed report that supports 
the absolute need for evidence-based research into the effects of using 
marijuana and, in particular, the cannabinoid components of marijuana, for 
patients with specific disease conditions.(iii)  Moreover, recent State-level 
public initiatives, including referenda in support of the medical use of 
marijuana, have generated additional interest in the medical community for 
high quality clinical investigation and comprehensive safety and 
effectiveness data.  

Against this backdrop are the real concerns regarding the toxicity of smoked 
marijuana.  Indeed, the IOM report emphasized that smoked marijuana is a 
crude drug delivery system that exposes patients to a significant number of 
harmful substances and that �if there is any future for marijuana as a 
medicine, it lies in its isolated components, the cannabinoids and their 
synthetic derivatives�.  As such, the IOM recommended that clinical trials 
should be conducted with the goal of developing safe delivery systems.

HHS recognizes the need for objective evaluations of the potential merits of 
cannabinoids for medical uses.  If a positive benefit is found, HHS also 
recognizes the need to stimulate development of alternative, safer dosage 
forms.  Through this document, HHS is announcing procedures that are intended 
to facilitate the research needed to evaluate these pending public health 
questions by making research-grade marijuana available for well-designed 
studies on a cost-reimbursable basis. 

II.  Availability of Marijuana for Research Purposes 

To facilitate research on the potential medical uses of cannabinoids, HHS has 
determined that it will make research-grade marijuana available on a cost-
reimbursable basis, subject to the priorities and conditions described in 
section III, below.  

HHS will also consider the extent to which a proposed study incorporates the 
trial design elements outlined by the participants in the 1997 NIH Workshop.  
Such studies are the most likely to yield high quality, scientifically valid 
data on the safety and effectiveness of cannabinoids.  The goal of this 
program must be to determine whether cannabinoid components of marijuana 
administered through an alternative delivery system can meet the standards 
enumerated under the Federal Food, Drug, and Cosmetic Act for commercial 
marketing of a medical product (see e.g., 21 U.S.C. 355).   As the IOM report 
stated, �Therefore, the purpose of clinical trials of smoked marijuana would 
not be to develop marijuana as a licensed drug, but such trials could be a 
first step towards the development of rapid-onset, nonsmoked cannabinoid 
delivery systems.�

III.  Elements for Considering Proposed Studies

The focus of HHS's program is the support of quality research for the 
development of clinically meaningful data.  HHS intends to make available a 
sufficient amount of research-grade marijuana to support those studies that 
are the most likely to yield usable, essential data.  However, it should be 
noted that NIDA�s supply of marijuana is subject to a number of constraints 
associated with the cultivation of a research-grade crop and that the supply 
at times may be variable.

For protocols submitted by non-NIH funded sources, institutional peer-review 
is strongly recommended prior to submission to HHS.  After submission, the 
scientific merits of each protocol will be evaluated through a Public Health 
Service interdisciplinary review process.  This process will take into 
consideration a number of factors, including the scientific quality of the 
proposed study, the quality of the organization�s peer-review process, and 
the objectives of the proposed research. For example:

The extent to which the protocol incorporates the elements of good clinical 
and laboratory research;

The extent to which the protocol describes an adequate and well-controlled 
clinical study to evaluate the safety and effectiveness of marijuana and its 
constituent cannabinoids in the treatment of a serious or life threatening 
condition;

The extent to which the protocol describes an adequate and well-controlled 
clinical study to evaluate the safety and effectiveness of marijuana and its 
constituent cannabinoids for a use for which there are no alternative 
therapies;

The extent to which the protocol describes a biopharmaceutical study designed 
to support the development of a dosage form alternative to smoking; 

The extent to which the protocol describes high-quality research designed to 
address basic, unanswered scientific questions about the effects of marijuana 
and its constituent cannabinoids or about the safety or toxicity of smoked 
marijuana.

In the event that supplies become limited, marijuana will be made available 
in the order of priority described below. 

1. Protocols that have been reviewed and funded by NIH. 

2. Protocols sponsored or conducted by other governmental organizations. 

3. Protocols sponsored or conducted by other sources. 

The sponsor of a proposed protocol must be able to demonstrate the ability to 
fully reimburse NIDA's contractor for the cost of research-grade marijuana 
supplied through the completion of the study. In addition, researchers who 
propose to conduct investigations in humans must be able to fulfill the Food 
and Drug Administration's investigational new drug (IND) requirements and 
must obtain a valid registration from the Drug Enforcement Administration 
(DEA) for research with Schedule I drugs.

IV.  Marijuana Trial Design Elements

A clinical study involving marijuana should include certain core elements, 
many of which reflect recommendations made by the 1997 NIH Workshop. A study 
that incorporates the NIH Workshop recommendations will be expected to yield 
useful data and therefore, will be more likely to be eligible to receive 
marijuana under the HHS program.  The full report can be accessed on the 
Internet at http://www.nih.gov/news/medmarijuana/MedicalMarijuana.htm.   HHS 
will consider if additional guidelines are needed on the essential elements of 
clinical trial design for medical marijuana studies.

HHS also notes that within each of the categories described in section III, 
preference will be given to those protocols that are designed around specific 
safety or efficacy endpoints.  Protocols for open-ended or "ongoing" trials 
that do not include ending dates are not likely to be eligible to receive 
marijuana. In addition, proposed protocols must be determined to be 
acceptable under FDA's standards for authorizing the clinical study of 
investigational new drugs, which state in part: 

FDA�s primary objectives in reviewing an IND are, in all phases of the 
investigation, to assure the safety and rights of subjects, and, in Phase 2 
and 3, to help assure that the quality of the scientific evaluation of drugs 
is adequate to permit an evaluation of the drug�s effectiveness and safety.  
Therefore, although FDA�s review of Phase 1 submissions will focus on 
assessing the safety of Phase 1 investigations, FDA�s review of Phases 2 and 
3 submissions will also include an assessment of the scientific quality of 
the clinical investigations and the likelihood that the investigations will 
yield data capable of meeting statutory standards for marketing approval.

21 CFR 312.22(a).

Finally, HHS intends to direct its program toward multi-patient clinical 
studies. As previously determined by the Public Health Service, single-
patient requests for marijuana raised a number of concerns including the fact 
that the single-patient IND process would not produce useful scientific 
information and we do not foresee that they would be supported under this 
program.

V.  Procedures for Obtaining Research-Grade Marijuana

Researchers who intend to conduct clinical studies of marijuana should first 
make an inquiry to NIDA to determine the availability and costs of marijuana.  
Such an inquiry must address the considerations outlined in sections III and 
IV of this document for establishing research priority.

Because research-grade marijuana will be provided to researchers on a cost-
reimbursable basis only, researchers also will be expected to include a plan 
for ensuring timely reimbursement for all costs associated with the 
cultivation and delivery of the marijuana. 

In addition, specific information (including full justification) should be 
provided as to the number and potency of marijuana cigarettes or bulk 
marijuana needed, and the timing of the intended use of the marijuana.  This 
information must be updated annually with NIDA in order that adequate 
supplies can be maintained and future needs estimated.  Continued provision 
of marijuana is subject to availability and to continued compliance with 
these policies and procedures and with all applicable statutes and 
regulations.

This information and requests to NIDA concerning availability and costs 
should be sent to:

Program Administrator
Drug Supply and Analytical Services
National Institute on Drug Abuse
6001 Executive Blvd
Bethesda, MD 20892

If NIDA determines that marijuana is available to support the study, NIDA 
will provide the researcher with authorization to reference NIDA's marijuana 
Drug Master File (DMF).

If the researcher is proposing a study in humans, after obtaining the right 
of reference to the DMF, the researcher must proceed through the FDA process 
for filing an IND application under 21 CFR part 312.  Information on the 
requirements for obtaining an IND can be found on the FDA web site at 
http://www.fda.gov.

In addition, all researchers must obtain from DEA registration to conduct 
research using a Schedule I controlled substance. Information on the 
requirements for obtaining a DEA registration for research with marijuana can 
be obtained following the process outlined in 21 CFR part 1301.   

VI.  Implementation 

This procedure will apply to the provision, through NIDA, of marijuana 
cigarettes (of varying THC content, including placebo), as well as bulk 
marijuana.  HHS will apply this procedure beginning on December 1, 1999.  HHS 
will re-evaluate these procedures periodically and determine within five 
years whether or not the procedures should be continued.  Requests for 
marijuana may be submitted prior to that time. However, shipments should not 
be expected before then and definitive information regarding costs may not be 
available until that time.

____________________________

i    Once implemented, this document will represent HHS�s current approach with 
     respect to biomedical research involving marijuana.  It does not create or 
     confer any rights for or on any person and does not operate to bind HHS or 
     the public.  An alternative approach may be used if such an approach would 
     satisfy all applicable legal requirements.

ii   Workshop on the Medical Utility of Marijuana: Report to the Director, 
     National Institutes of Health.  National Institutes of Health,
     February 19-21, 1997. 

iii  "Marijuana and Medicine: Assessing the Science Base", Institute of Medicine, 
     March 17, 1999.
  

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