[Federal Register Volume 66, Number 75 (Wednesday, April 18, 2001)]
[Notices]
[Pages 20038-20076]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 01-9306]



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Part II





Department of Justice





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Drug Enforcement Agency



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Denial of Petition; Notice

Federal Register / Vol. 66, No. 75 / Wednesday, April 18, 2001 / 
Notices

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DEPARTMENT OF JUSTICE

Drug Enforcement Administration


Notice of Denial of Petition

    By letter dated March 20, 2001, the Drug Enforcement Administration 
(DEA) denied a petition to initiate rulemaking proceedings to 
reschedule marijuana. Because DEA believes that this matter is of 
particular interest to members of the public, the agency is publishing 
below the letter sent to the petitioner (denying the petition), along 
with the supporting documentation that was attached to the letter.

    Dated: March 28, 2001.
Donnie R. Marshall,
Administrator.

U.S. Department of Justice,

Drug Enforcement Administration, Washington, D.C. 20537

March 20, 2001.

Jon Gettman:

    Dear Mr. Gettman: On July 10, 1995, you petitioned the Drug 
Enforcement Administration (DEA) to initiate rulemaking proceedings 
under the rescheduling provisions of the Controlled Substances Act 
(CSA). Specifically, you petitioned DEA to propose rules, pursuant 
to 21 U.S.C. 811(a), that would amend the schedules of controlled 
substances with respect to the following controlled substances: 
marijuana; tetrahydrocannabinols; dronabinol; and nabilone. Although 
you grouped these substances together in your petition, the 
scheduling analysis differs for each. To avoid confusion, DEA is 
providing you with a separate response for each of the controlled 
substances that you proposed be rescheduled. This letter responds to 
your petition to reschedule marijuana.

Summary

    You requested that DEA remove marijuana from schedule I based on 
your assertion that ``there is no scientific evidence that [it has] 
sufficient abuse potential to warrant schedule I or II status under 
the [CSA].'' In accordance with the CSA rescheduling provisions, DEA 
gathered the necessary data and forwarded that information and your 
petition to the Department of Health and Human Services (HHS) for a 
scientific and medical evaluation and scheduling recommendation. HHS 
concluded that marijuana does have a high potential for abuse and 
therefore recommended that marijuana remain in schedule I. Based on 
the HHS evaluation and all other relevant data, DEA has concluded 
that there is no substantial evidence that marijuana should be 
removed from schedule I. Accordingly, your petition to initiate 
rulemaking proceedings to reschedule marijuana is hereby denied.

Detailed Explanation

A. Statutory Requirements and Procedural History

    The CSA provides that the schedules of controlled substances 
established by Congress may be amended by the Attorney General in 
rulemaking proceedings prescribed by the Administrative Procedure 
Act. 21 U.S.C. 811(a). The Attorney General has delegated this 
authority to the Administrator of DEA. 28 CFR 0.100.
    As you have done, any interested party may petition the 
Administrator to initiate rulemaking proceedings to reschedule a 
controlled substance. 21 U.S.C. 811(a); 21 CFR 1308.43(a). Before 
initiating such proceedings, the Administrator must gather the 
necessary data and request from the Secretary of HHS a scientific 
and medical evaluation and recommendation as to whether the 
controlled substance should be rescheduled as the petitioner 
proposes. 21 U.S.C. 811(b); 21 CFR 1308.43(d). The Secretary has 
delegated this function to the Assistant Secretary for Health.\1\
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    \1\ As set for in a memorandum of understanding entered in to by 
HHS, the Food and Drug Administration (FDA), and the National 
Institute on Drug Abuse (NIDA), FDA acts as the lead agency within 
HHS in carrying out the Secretary's scheduling responsibilities 
under the CAS, with the concurrence of NIDA. 50 FR 9518 (1985).
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    The recommendations of the Assistant Secretary are binding on 
the Administrator with respect to scientific and medical matters. 
Id. If the Administrator determines that the evaluations and 
recommendations of the Assistant Secretary and ``all other relevant 
data'' constitute substantial evidence that the drug that is the 
subject of the petition should be subject to lesser control or 
removed entirely from the schedules, he shall initiate rulemaking 
proceedings to reschedule the drug or remove it from the schedules 
as the evidence dictates. 21 U.S.C. 811(b); 21 CFR 1308.43(e). In 
making such a determination, the Administrator must consider eight 
factors:
    (1) The drug's actual or relative potential for abuse;
    (2) Scientific evidence of its pharmacological effect, if known;
    (3) The state of current scientific knowledge regarding the 
drug;
    (4) Its history and current pattern of abuse;
    (5) The scope, duration, and significance of abuse;
    (6) What, if any, risk there is to the public health;
    (7) The drug's psychic or physiological dependence liability; 
and
    (8) Whether the drug is an immediate precursor of a substance 
already controlled under the CSA.

21 USC 811(c).
    In this case, you submitted your petition by letter dated March 
10, 1995. After gathering the necessary data, DEA referred the 
petition to HHS on December 17, 1997, and requested from HHS a 
scientific and medical evaluation and scheduling recommendation. HHS 
forwarded its scientific and medical evaluation and scheduling 
recommendation to DEA on January 17, 2001.

B. HHS Scientific and Medical Evaluation and Other Relevant Data 
Considered by DEA

    Attached to this letter is the scientific and medical evaluation 
and scheduling recommendation that HHS submitted to DEA.\2\ Also 
attached is a document prepared by DEA that specifies other data 
relevant to your petition that DEA considered.
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    \2\ To avoid confusion, those parts of the HHS document that are 
not relevant to your petition with respect to marijuana (i.e., those 
parts that are relevant only to the scheduling of 
tetrahydrocannabinols, dronabinol, or nabilone) have been redacted 
from the attachment. The HHS evaluation of these other substances 
will be addressed when DEA responds (in separate letters) to your 
petitions with respect to these other substances.
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C. Basis for Denial of Your Petition: The Evidence Demonstrates That 
Marijuana Does Have A High Potential For Abuse

    Your petition rests on your contention that marijuana does not 
have a ``high potential for abuse'' commensurate with schedule I or 
II of the CSA. The Assistant Secretary has concluded, based on 
current scientific and medical evidence, that marijuana does have a 
high potential for abuse commensurate with schedule I. The 
additional data gathered by DEA likewise reveals that marijuana has 
a high potential for abuse. Indeed, when the HHS evaluation is 
viewed in combination with the additional data gathered by DEA, the 
evidence overwhelmingly leads to the conclusion that marijuana has a 
high potential for abuse.
    Accordingly, there is no statutory basis for DEA to grant your 
petition to initiate rulemaking proceedings to reschedule marijuana. 
For this reason alone, your petition must be denied.

D. A Schedule I Drug With a High Potential For Abuse and No Currently 
Accepted Medical Use or Safety for Use Must Remain Classified In 
Schedule I

    DEA's denial of your petition is based exclusively on the 
scientific and medical findings of HHS, with which DEA concurs, that 
lead to the conclusion that marijuana has a high potential for 
abuse. Nonetheless, independent of this scientific and medical basis 
for denying your petition, there is a logical flaw in your proposal 
that should be noted.
    You do not assert in your petition that marijuana has a 
currently accepted medical use in treatment in the United States or 
that marijuana has an accepted safety for use under medical 
supervision. Indeed, the HHS scientific and medical evaluation 
reaffirms expressly that marijuana has no currently accepted medical 
use in treatment in the United States and a lack of accepted safety 
for use under medical supervision.
    Nor do you dispute that marijuana is a drug of abuse. That is, 
you do not contend that marijuana has no potential for abuse such 
that it should be removed entirely from the CSA schedules. Rather, 
your contention is that marijuana has less than a ``high potential 
for abuse'' commensurate with schedules I and II and, therefore, it 
cannot be classified in either of these two schedules.
    Congress established only one schedule--schedule I--for drugs of 
abuse with ``no currently accepted medical use in treatment in the 
United States'' and ``lack of accepted safety for use * * * under 
medical supervision.'' 21 USC 812(b). To be classified in schedules 
II through V, a drug of abuse

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must have a ``currently accepted medical use in treatment in the 
United States.'' \3\ Id. This is why the CSA allows practitioners to 
prescribe only those controlled substances that are listed in 
schedules II through V. 21 USC 829. Drugs listed in schedule I, by 
contrast, may not be prescribed for patient use; they may only be 
dispensed by practitioners who are conducting FDA-approved research 
and have obtained a schedule I research registration from DEA. 21 
USC 823(f); 21 CFR 5.10(a)(9), 1301.18, 1301.32.
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    \3\ A controlled substance in schedule II must have either ``a 
currently accepted medical use in treatment in the United States or 
a currently accepted medical use with severe restrictions.'' 21 USC 
812(b)(2)(B).
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    That schedule I controlled substances are characterized by a 
lack of accepted medical use was recently reiterated by Congress, 
when it declared, in a provision entitled, ``NOT LEGALIZING 
MARIJUANA FOR MEDICINAL USE'':
    It is the sense of the Congress that--
    (1) certain drugs are listed on Schedule I of the Controlled 
Substances Act if they have a high potential for abuse, lack any 
currently accepted medical use in treatment, and are unsafe, even 
under medical supervision;
    (2) the consequences of illegal use of Schedule I drugs are well 
documented, particularly with regard to physical health, highway 
safety, and criminal activity;
    (3) pursuant to section 401 of the Controlled Substances Act, it 
is illegal to manufacture, distribute, or dispense marijuana, 
heroin, LSD, and more than 100 other Schedule I drugs;
    (4) pursuant to section 505 of the Federal Food, Drug and 
Cosmetic Act, before any drug can be approved as a medication in the 
United States, it must meet extensive scientific and medical 
standards established by the Food and Drug Administration to ensure 
it is safe and effective;
    (5) marijuana and other Schedule I drugs have not been approved 
by the Food and Drug Administration to treat any disease or 
condition.
* * * * *
Pub. L. No. 105-277, Div. F., 112 Stat. 2681-760 to 2681-761 (1998) 
(emphasis added).
    Thus, when it comes to a drug that is currently listed in 
schedule I, if it is undisputed that such drug has no currently 
accepted medical use in treatment in the United States and a lack of 
accepted safety for use under medical supervision, and it is further 
undisputed that the drug has at least some potential for abuse 
sufficient to warrant control under the CSA, the drug must remain in 
schedule I. In such circumstances, placement of the drug in 
schedules II through V would conflict with the CSA since such drug 
would not meet the criterion of ``a currently accepted medical use 
in treatment in the United States.'' 21 USC 812(b).
    Therefore, even if one were to assume, theoretically, that your 
assertions about marijuana's potential for abuse were correct (i.e., 
that marijuana had some potential for abuse but less than the ``high 
potential for abuse'' commensurate with schedules I and II), 
marijuana would not meet the criteria for placement in schedules III 
through V since it has no currently accepted medical use in 
treatment in the United States--a determination that is reaffirmed 
by HHS in the attached medical and scientific evaluation.
    For the foregoing reasons, your petition to reschedule marijuana 
cannot be granted under the CSA and is, therefore, denied.

      Sincerely,

Donnie R. Marshall,
Administrator.
Attachments.

Department of Health and Human Services,

Office of the Secretary, Office of the Public Health and Science, 
Assistant Secretary for Health, Surgeon General, Washington, D.C. 
20201.

January 17, 2001.

Mr. Donnie R. Marshall,
Deputy Administrator, Drug Enforcement Administration, Washington, 
D.C. 20537.

Dear Mr. Marshall: In response to your request dated December 17, 
1997, and pursuant to the Controlled Substances Act (CSA), 21 U.S.C. 
Sec. 811 (b), (c), and (f), the Department of Health and Human 
Services (DHHS) recommends that marijuana * * * continue to be 
subject to control under Schedule I. * * * Marijuana and the 
tetrahydrocannabinols are currently controlled under Schedule I of 
the CSA. Marijuana continues to meet the three criteria for placing 
a substance in Schedule I of the CSA under 21 U.S.C. 812(b)(1). As 
discussed in the attached analysis, marijuana has a high potential 
for abuse, has no currently accepted medical use in treatment in the 
United States, and has a lack of accepted safety for use under 
medical supervision. Accordingly, HHS recommends that marijuana * * 
* continue to be subject to control under Schedule I of the CSA.
    You will find enclosed two documents prepared by FDA's 
Controlled Substance Staff that are the bases for the 
recommendations.

      Sincerely yours,
David Satcher,
Assistant Secretary for Health and Surgeon General.
Enclosure.

Basis for the Recommendation for Maintaining Marijuana in Schedule 
I of the Controlled Substances Act

A. Background

    On July 10, 1995, Mr. Jon Gettman submitted a petition to the Drug 
Enforcement Administration (DEA) requesting that proceedings be 
initiated to repeal the rules and regulations that place marijuana and 
the tetrahydrocannabinols in Schedule I of the Controlled Substances 
Act (CSA) and dronabinol and nabilone in Schedule II of the CSA. The 
petition contends that evidence of abuse potential is insufficient for 
each substance or class of substances to be controlled in Schedule I or 
II of the CSA. In December 1997, the DEA Administrator requested that 
the Department of Health and Human Services (DHHS) develop scientific 
and medical evaluations and recommendations as to the proper scheduling 
of the substances at issue, pursuant to 21 U.S.C. 811(b).
    This document responds to the portion of the petition that concerns 
marijuana * * *.
    In accordance with 21 U.S.C. 811(b), the DEA has gathered 
information, and the Secretary of DHHS has considered eight factors in 
a scientific and medical evaluation, to determine how to schedule and 
control marijuana (Cannabis sativa) under the CSA. The eight factors 
are: actual or relative potential for abuse, scientific evidence of 
pharmacological effects, scientific knowledge about the drug or 
substance in general, history and current patterns of abuse, the scope 
and duration and significance of abuse, the risk (if any) to public 
health, psychic or physiologic dependence liability, and whether the 
substance is an immediate precursor of a substance that is already 
controlled. If appropriate, the Secretary must also make three 
findings--related to a substance's abuse potential, legitimate medical 
use, and safety or dependence liability--and then a recommendation. 
This evaluation presents scientific and medical knowledge under the 
eight factors, findings in the three required areas, and a 
recommendation.
    Administrative responsibilities for evaluating a substance for 
control under the CSA are performed by the Food and Drug Administration 
(FDA), with the concurrence of the National Institute on Drug Abuse 
(NIDA), as described in the Memorandum of Understanding (MOU) of March 
8, 1985 (50 FR 9518-20).
    Pursuant to 21 U.S.C. 811(c), the eight factors pertaining to the 
scheduling of marijuana are considered below. The weight of the 
scientific and medical evidence considered under these factors supports 
the three findings that: (1) Marijuana has a high potential for abuse, 
(2) marijuana has no currently accepted medical use in treatment in the 
United States, and (3) there is a lack of accepted evidence about the 
safety of using marijuana under medical supervision.

B. Evaluating Marijuana Under the Eight Factors

    This section presents scientific and medical knowledge about 
marijuana under the eight required factors.

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1. Its Actual or Relative Potential for Abuse
    The CSA defines marijuana as the following:

    All parts of the plant Cannabis Sativa L., whether growing or 
not; the seeds thereof; the resin extracted from any part of such 
plant; and every compound, manufacture, salt, derivative, mixture, 
or preparation of such plant, its seeds or resin. Such term does not 
include the mature stalks of such plant, fiber produced from such 
stalks, oil or cake made from the seeds of such plant, any other 
compound, manufacture, salt, derivative, mixture, or preparation of 
such mature stalks (except the resin extracted therefrom), fiber, 
oil, or cake, or the sterilized seed of such plant which is 
incapable of germination.
21 U.S.C. 802(16).

    The term ``abuse'' is not defined in the CSA. However, the 
legislative history of the CSA suggests the following in determining 
whether a particular drug or substance has a potential for abuse:
    a. Individuals are taking the substance in amounts sufficient to 
create a hazard to their health or to the safety of other individuals 
or to the community.
    b. There is a significant diversion of the drug or substance from 
legitimate drug channels.
    c. Individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner licensed 
by law to administer such substances.
    d. The substance is so related in its action to a substance already 
listed as having a potential for abuse to make it likely that it will 
have the same potential for abuse as such substance, thus making it 
reasonable to assume that there may be significant diversions from 
legitimate channels, significant use contrary to or without medical 
advice, or that it has a substantial capability of creating hazards to 
the health of the user or to the safety of the community.

Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. 
No. 91-1444, 91st Cong., Sess. 1 (1970) reprinted in U.S.C.C.A.N. 4566, 
4603.
    In considering these concepts in a variety of scheduling analyses 
over the last three decades, the Secretary has analyzed a range of 
factors when assessing the abuse liability of a substance. These 
factors have included the prevalence and frequency of use in the 
general public and in specific sub-populations, the amount of the 
material that is available for illicit use, the ease with which the 
substance may be obtained or manufactured, the reputation or status of 
the substance ``on the street'', as well as evidence relevant to 
population groups that may be at particular risk.
    Abuse liability is a complex determination with many dimensions. 
There is no single test or assessment procedure that, by itself, 
provides a full and complete characterization. Thus, no single measure 
of abuse liability is ideal. Scientifically, a comprehensive evaluation 
of the relative abuse potential of a drug substance can include 
consideration of the drug's receptor binding affinity, preclinical 
pharmacology, reinforcing effects, discriminative stimulus effects, 
dependence producing potential, pharmacokinetics and route of 
administration, toxicity, assessment of the clinical efficacy-safety 
database relative to actual abuse, clinical abuse liability studies and 
the public health risks following introduction of the substance to the 
general population. It is important to note that abuse may exist 
independent of a state of physical dependence, because drugs may be 
abused in doses or in patterns that do not induce physical dependence.
    Animal data and epidemiological data are both used in determining a 
substance's abuse liability. While animal data may help the Secretary 
draw conclusions on the abuse liability of a substance, data regarding 
human abuse, if available, is given greater weight. For example, even 
if a compound fails to display abuse liability in animal laboratory 
testing, positive evidence of abuse liability in humans is given 
greater weight. Epidemiological data can also be an important indicator 
of actual abuse and may, in some circumstances, be given greater weight 
than laboratory data. Thus, in situations where the epidemiological 
data indicates that a substance is abused, despite the lack of positive 
abuse liability indications in animal or human laboratory testing, the 
abuse liability determination may rest more heavily on the 
epidemiological data. Finally, evidence of clandestine production and 
illicit trafficking of a substance are also important factors to 
consider as this evidence sheds light on both the demand for a 
substance as well as the ease with which it can be obtained.
    The Secretary disagrees with Mr. Gettman's assertion that ``[t]he 
accepted contemporary legal convention for evaluating the abuse 
potential of a drug or substance is the relative degree of self-
administration the drug induces in animal subjects.'' As discussed 
above, self-administration tests that identify whether a substance is 
reinforcing in animals are but one component of the scientific 
assessment of the abuse potential of a substance. Positive indicators 
of human abuse liability for a particular substance, whether from 
laboratory studies or epidemiological data, are given greater weight 
than animal studies suggesting the same compound has no abuse 
potential.
    Throughout his petition, Mr. Gettman argues that while many people 
``use'' marijuana, few ``abuse'' it. He appears to equate abuse with 
the level of physical dependence and toxicity resulting from marijuana 
use. Thus, he appears to be arguing that a substance that causes only 
low levels of physical dependence and toxicity must be considered to 
have a low potential for abuse. The Secretary does not agree with this 
argument. Physical dependence and toxicity are not the only factors 
that are considered in determining a substance's abuse potential. The 
actual use and frequency of use of a substance, especially when that 
use may result in harmful consequences such as failure to fulfill major 
obligations at work or school, physical risk-taking, or even substance-
related legal problems, are indicative of a substance's abuse 
potential.
    a. There is evidence that individuals are taking the substance in 
amounts sufficient to create a hazard to their health or to the safety 
of other individuals or to the community.
    Marijuana is a widely used substance. The pharmacology of the 
psychoactive constituents of marijuana (including delta\9\-THC, the 
primary psychoactive ingredient in marijuana) has been studied 
extensively in animals and humans and is discussed in more detail below 
in Section 2, ``Scientific Evidence of its Pharmacological Effects, if 
Known.'' Although it is difficult to determine the full extent of 
marijuana abuse, extensive data from the National Institute on Drug 
Abuse (NIDA) and from the Substance Abuse Mental Health Services 
Administration (SAMHSA) are available. These data are discussed in 
detail in Section 4 ``Its History and Current Pattern of Abuse;'' 
Section 5, ``The Scope, Duration, and Significance of Abuse;'' and 
Section 6, ``What, if any Risk There is to the Public Health.''
    According to the National Household Survey on Drug Abuse (NHSDA), 
of the 14.8 million Americans who used illicit drugs on a monthly basis 
in 1999, 11.2 million used marijuana. In 1998, 1.6 million children 
between the ages of 12 and 17 used marijuana for the first time. (See 
the discussion of the 1999 NHSDA in Section 4). A 1999 survey of 8th, 
10th, and 12th grade students indicates that marijuana is the most 
widely used illicit drug in this age group. By 12th grade, 37.8% of 
students report having used marijuana in the past year, and 23.1% 
report using it monthly. (See the

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discussion of the Monitoring the Future Study in Section 4). Primary 
marijuana abuse accounts for 13% of the admissions to treatment 
facilities for substance abuse, with 92% of those admitted having used 
marijuana for the first time by age 18. (See discussion of the 
Treatment Episode Data Set in Section 4).
    The Drug Abuse Warning Network (DAWN) is a national probability 
survey of hospitals with emergency departments (EDs). DAWN is designed 
to obtain information on ED episodes that are induced by or related to 
the use of an illegal drug or the non-medical use of a legal drug. DAWN 
recently reported 87,150 ED drug mentions for marijuana/ hashish in 
1999, representing 16 % of all drug-related episodes in 1999. (See 
discussion of DAWN in Section 4). In 1999, DAWN data show that out of 
664 medical examiner marijuana-related episodes, there were 187 deaths 
in persons who had used marijuana alone. While marijuana has a low 
level of toxicity when compared to other drugs of abuse, there are a 
number of risks resulting from both acute and chronic use of marijuana. 
These risks are discussed in full in sections 2 and 6 below.
    b. There is significant diversion of the substance from legitimate 
drug channels.
    Because cannabis is currently available through legitimate channels 
for research purposes only, there is limited legitimate use of this 
substance and thus limited potential for diversion. The lack of 
significant diversion of investigational supplies may also result from 
the ready availability of cannabis of equal or greater potency through 
illicit channels.
    The magnitude of the demand for marijuana is, however, evidenced by 
the Drug Enforcement Administration (DEA) / Office of National Drug 
Control Policy (ONDCP) statistics. Data on marijuana seizures can often 
highlight trends in the overall trafficking patterns. The DEA's 
Federal-Wide Drug Seizure System (FDSS) provides information on total 
federal drug seizures. FDSS reports total federal seizures of 699 
metric tons of marijuana in fiscal year 1997, 825 metric tons in fiscal 
year 1998 and 1,175 metric tons in fiscal year 1999 (ONDCP, 2000).
    c. Individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner licensed 
by law to administer such substances.
    The 1998 NHSDA suggests that 6.8 million individuals use marijuana 
on a weekly basis (SAMHSA, 1998), confirming that marijuana has 
reinforcing properties for many individuals. The FDA has not approved a 
new drug application for marijuana, although research under several 
INDs is currently active. Based on the large number of individuals who 
use marijuana, it can be concluded that the majority of individuals 
using cannabis do so on their own initiative, not on the basis of 
medical advice from a practitioner licensed to administer the drug in 
the course of professional practice.
    d. The substance is so related in its action to a substance already 
listed as having a potential for abuse to make it likely that it will 
have the same potential for abuse as such substance, thus making it 
reasonable to assume that there may be significant diversions from 
legitimate channels, significant use contrary to or without medical 
advice, or that it has a substantial capability of creating hazards to 
the health of the user or to the safety of the community.
    Two drug products that contain cannabinoid compounds that are 
structurally related to the active components in marijuana are already 
regulated under the CSA. These are Marinol (dronabinol, delta\9\-THC), 
which is a Schedule III drug, and nabilone, which is a Schedule II 
drug. All other cannabinoid compounds that are structurally related to 
the active components in marijuana are listed as Schedule I drugs under 
the CSA. Cannabinoid compounds constitute a distinct pharmacological 
class that is unrelated to other drugs currently listed in the CSA. The 
primary psychoactive compound in botanical marijuana is delta\9\-
tetrahydrocannabinol (delta\9\-THC). Other cannabinoids also present in 
the marijuana plant likely contribute to the psychoactive effects. 
Individuals administer the constituents of marijuana by burning the 
material and inhaling (smoking) many of its combustible and vaporized 
products. The route of administration of a drug is one component of its 
abuse potential. Most psychoactive drugs exert their maximum subjective 
effects when blood levels of the drug are rapidly increased. Inhalation 
of drugs permits a rapid delivery and distribution of the drug to the 
brain. The intense psychoactive drug effect, which can be rapidly 
achieved by smoking, is often called a ``rush'' and generally is 
considered to be the effect desired by the abuser. This effect explains 
why marijuana abusers prefer the inhalation, intravenous or intranasal 
routes rather than oral routes of administration. Such is also the case 
with cocaine, opium, heroin, phencyclidine, and methamphetamine (Wesson 
& Washburn, 1990).
2. Scientific Evidence of Its Pharmacological Effects, If Known
    We concur with the petitioner that there is abundant scientific 
data available on the neurochemistry, toxicology, and pharmacology of 
marijuana. This section includes a scientific evaluation of marijuana's 
neurochemistry and pharmacology, central nervous system effects 
including human and animal behavior, pharmacodynamics of central 
nervous system effects, cognitive effects, cardiovascular and autonomic 
effects, endocrine system effects and immunological system effects. The 
overview presented below relies upon the most current research 
literature on cannabinoids.

Neurochemistry and Pharmacology of Marijuana

    To date, a total of 483 natural constituents have been identified 
in marijuana of which approximately 66 belong to the general group 
known as cannabinoids (Ross and ElSohly, 1995). The cannabinoids appear 
to be unique to marijuana, and most of those occurring naturally have 
already been identified. Within the cannabinoids, delta\9\-
tetrahydrocannabinol (delta\9\-THC) is considered the major 
psychoactive constituent of marijuana. Since the elucidation of the 
structure and discovery of the function of delta\9\-THC, in 1964 by 
Gaoni and Mechoulam, cannabis and cannabinoid research has flourished. 
Substantial discoveries on the pharmacology, biochemistry and 
behavioral mechanisms of action of the cannabinoids have been 
accomplished, and laid the scientific foundations for a better 
understanding of the effects of marijuana.
    There is conclusive evidence of the existence of at least two 
cannabinoid receptors, CB1 and CB2, and it is now 
known that some of the pharmacological effects of cannabinoids are 
mediated through activation of these receptors. The cannabinoid 
receptors belong to the G-protein-coupled receptors family and present 
a typical seven transmembrane-spanning domain structure. Many G-protein 
coupled receptors are linked to adenylate cyclase, and stimulation of 
these receptors might result, either in inhibition or activation of 
adenylate cyclase, depending on the receptor system. Cannabinoid 
receptors are linked to an inhibitory G protein (Gi), meaning that when 
activated, inhibition of the activity of adenylate cyclase occurs, thus 
preventing the conversion of ATP to the second messenger cyclic AMP 
(cAMP). Examples of inhibitory-coupled receptors include opioid,

[[Page 20042]]

muscarinic," 2-adrenoreceptors, dopamine (D2) and 
serotonin (5-HT1) among others. The pharmacological 
relevance of the adenylate cyclase inhibition has been difficult to 
determine (Adams and Martin, 1996).
    Advances in molecular biology allowed the cloning of a cannabinoid 
receptor (Matsuda et al., 1990), first from rat brain origin followed 
by the cloning of the human receptor (Gerard et al., 1991) therefore 
offering definitive evidence for a specific cannabinoid receptor. 
Autoradiographic studies have provided information on the distribution 
of cannabinoid receptors. CB1 receptors are present in the 
brain and spinal cord and in certain peripheral tissues. The 
distribution pattern of these receptors within the central nervous 
system is heterogeneous. It is believed that the localization of these 
receptors in various regions of the brain, such as basal ganglia, 
cerebellum, hippocampus and cerebral cortex, may explain cannabinoid 
interference with movement coordination and effects on memory and 
cognition. Concentration of CB1 receptors is considerably 
lower in peripheral tissues than in the central nervous system 
(Henkerham et al., 1990 and 1992). CB2 receptors have been 
detected only outside the central nervous system. Their occurrence has 
been shown to be primarily in immune tissues such as leukocytes, spleen 
and tonsils and it is believed that the CB2-type receptor is 
responsible for mediating the immunological effects of cannabinoids 
(Galiegui et al., 1995).
    Recently it has been shown that CB1 but not 
CB2 receptors inhibit N- and Q type calcium channels and 
activate inwardly rectifying potassium channels. Inhibition of the N-
type calcium channels decreases neurotransmitter release from several 
tissues and this may the mechanism by which cannabinoids inhibit 
acetylcholine, noradrenaline and glutamate release from specific areas 
of the brain. These effects might represent a potential cellular 
mechanism underlying the antinociceptive and psychoactive effects of 
cannabinoids (Ameri, 1999).
    Several synthetic cannabinoid agonists have been synthesized and 
characterized and selective antagonists for both receptors have been 
identified. In 1994, SR-141716A, the first selective antagonist with 
CB1 selectivity was identified, and more recently the 
selective CB2 receptor antagonist, SR-144528, was described 
(Rinaldi-Carmona et al., 1994 and 1998). In general, antagonists have 
proven to be invaluable tools in pharmacology. They allow the 
identification of key physiological functions by the receptors, through 
the blockade of their responses.
    Delta\9\-THC displays similar affinity for CB1 and 
CB2 receptors but behaves as a weak agonist for 
CB2 receptors as judged by inhibition of adenylate cyclase. 
The identification of synthetic cannabinoid ligands deprived of the 
typical THC-like psychoactive properties, that selectively bind to 
CB2 receptors, supports the idea that the psychotropic 
effects of cannabinoids are mediated through the activation of 
CB1-receptors (Hanus et al., 1999). Furthermore, cannabinoid 
agonists such as delta\9\-THC and the synthetic ones, WIN-55,212-2 and 
CP-55,940, produce hypothermia, analgesia, hypoactivity and cataplexy. 
These effects are reversed by the selective CB1 antagonist, 
SR-141716A, providing good evidence for the involvement of a 
CB1 receptor mediated mechanism.
    In addition, the discovery of the endogenous cannabinoid receptor 
agonists, anandamide and arachidonyl glycine (2-AG) confirmed the 
belief of a central cannabinoid neuromodulatory system. Indeed, 
cannabinoid and their endogenous ligands are present in central as well 
as peripheral tissues. Mechanisms for the synthesis and metabolism of 
anandamide have been described. The physiological roles of endogenous 
cannabinoids are not yet fully characterized, although it has been the 
target of large research efforts (Martin et al., 1999).
    In conclusion, progress in cannabinoid pharmacology, including the 
characterization of the cannabinoid receptors, isolation of endogenous 
cannabinoid ligands, synthesis of agonists and antagonists with diverse 
degree of affinity and selectivity for cannabinoid receptors, have 
provided the foundation for the elucidation of the specific effects 
mediated by cannabinoids and their roles in psychomotor disorders, 
memory, cognitive functions, analgesia, antiemesis, intraocular and 
systemic blood pressure modulation, broncodilation, and inflammation.
    The reinforcing properties of a number of commonly abused drugs 
such as amphetamine, cocaine, alcohol, morphine and nicotine, have been 
explained by the effects of these drugs in the activation of 
dopaminergic pathways in certain areas of the brain and in particular 
the mesolimbic dopaminergic system (Koob, 1992). It has been 
demonstrated that delta\9\-THC increases dopamine activity in reward 
relevant circuits in the brain (French, 1997; Gessa, et al. 1998), but 
the mechanism of these effects and the relevance of these findings in 
the context of the abuse potential of marijuana is still unknown.

Central Nervous System Effects

Human Behavioral Effects
    As with other psychoactive drugs, the response that an individual 
has to marijuana is dependent on the set (psychological and emotional 
orientation) and setting (circumstances) under which the individual 
takes the drug. Thus, if an individual uses marijuana while in a happy 
state of mind among good friends, the responses are likely to be 
interpreted as more positive than if that individual uses the drug 
during a crisis while alone.
    The mental and behavioral effects of marijuana can vary widely 
among individuals, but common responses, described by Wills (1998) and 
others (Adams and Martin 1996; Hollister 1986a, 1988a; Institute of 
Medicine 1982) are listed below:
    (1) Dizziness, nausea, tachycardia, facial flushing, dry mouth and 
tremor can occur initially
    (2) Merriment, happiness and even exhilaration at high doses
    (3) Disinhibition, relaxation, increased sociability, and 
talkativeness
    (4) Enhanced sensory perception, giving rise to increased 
appreciation of music, art and touch
    (5) Heightened imagination leading to a subjective sense of 
increased creativity
    (6) Time distortions
    (7) Illusions, delusions and hallucinations are rare except at high 
doses
    (8) Impaired judgement, reduced co-ordination and ataxia, which can 
impede driving ability or lead to an increase in risk-taking behavior
    (9) Emotional lability, incongruity of affect, dysphoria, 
disorganized thinking, inability to converse logically, agitation, 
paranoia, confusion, restlessness, anxiety, drowsiness and panic 
attacks may occur, especially in inexperienced users or in those who 
have taken a large dose
    (10) Increased appetite and short-term memory impairment are common
    Humans demonstrate a preference for higher doses of marijuana 
(1.95% delta9-THC) over lower doses (0.63% 
delta9-THC) (Chaitand Burke, 1994), similar to the dose 
preference exhibited for many other drugs of abuse.
Animal Behavioral Effects
     Predictors of Reinforcing Effects (Self-Administration and 
Conditioned Place Preference)
    One indicator of whether a drug will be reinforcing in humans is 
the self-administration test in animals. Self-

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administration of marijuana, LSD, sigma receptor agonists, or 
cholinergic antagonists is difficult to demonstrate in animals. 
However, when it is known that humans voluntarily consume a particular 
drug for its pleasurable effects, the inability to establish self-
administration with that drug in animals has no practical importance. 
This is because the animal test is only useful as a rough predictor of 
human behavioral response in the absence of naturalistic data. Thus, 
the petitioner is incorrect that the accepted legal convention for 
abuse potential is self-administration in animals and that because 
marijuana does not induce self-administration in animals, it has a 
lower abuse potential than drugs that easily induce self-administration 
in animals. Similarly, the petitioner is incorrect that the difficulty 
in inducing self-administration of marijuana in animals is due to a 
lack of effect on dopamine receptors. In fact, dopamine release can be 
stimulated indirectly by marijuana, following direct action of the drug 
on cannabinoid receptors. However, it is important to note that while 
self-administration in animals has been correlated with dopamine 
function, both pleasurable and painful stimuli can evoke dopaminergic 
responses. Dopamine functioning does not determine scheduling under the 
CSA.
    Naive animals will not typically self-administer cannabinoids when 
they must choose between saline and a cannabinoid. However, a recent 
report shows that when squirrel monkeys are first trained to self-
administer intravenous cocaine, they will continue to bar-press at the 
same rate when THC is substituted for cocaine, at doses that are 
comparable to those used by humans who smoke marijuana (Tanda et al., 
2000). This effect was blocked by the cannabinoid receptor antagonist, 
SR 141716. These data demonstrate that under specific pretreatment 
conditions, an animal model of reinforcement by cannabinoids now exists 
for future investigations. Additionally, mice have been reported to 
self-administer WIN 55212, a CB1 receptor agonist with a 
non-cannabinoid structure (Martellotta et al., 1998). There may be a 
critical dose-dependent effect, though, since aversive effects, rather 
than reinforcing effects, have been described in rats with high doses 
of WIN 55212 (Chaperon et al., 1998) as well as delta9-THC 
(Sanudo-Pena et al., 1997). The cannabinoid antagonist, SR 141716, 
counteracted these aversive effects.
    The conditioned place preference (CPP) test also functions as a 
predictor of reinforcing effects. Animals show CPP to cannabinoids, but 
only at mid-dose levels. However, cannabinoid antagonists also induce 
CPP, suggesting that occupation of the cannabinoid receptor itself, may 
be responsible.
     Drug Discrimination Studies
    Animals, including monkeys and rats (Gold et al., 1992) as well as 
humans (Chait, 1988) can discriminate cannabinoids from other drugs or 
placebo. Discriminative stimulus effects of delta\9\-THC are 
pharmacologically specific for marijuana-containing cannabinoids 
(Balster and Prescott, 1992, Barrett et al., 1995, Browne and Weissman, 
1981, Wiley et al., 1993, Wiley et al., 1995). Additionally, the major 
active metabolite of delta\9\-THC, 11-OH-delta\9\-THC, also generalized 
to the stimulus cue elicited by delta\9\-THC (Browne and Weissman, 
1981). Twenty-two other cannabinoids found in marijuana also fully 
substituted for delta\9\-THC. The discriminative stimulus effects of 
the cannabinoid group appear to provide unique effects because 
stimulants, hallucinogens, opioids, benzodiazepines, barbiturates, NMDA 
antagonists and antipsychotics have not been shown to substitute for 
delta\9\-THC.

Pharmacodynamics of CNS Effects

    Psychoactive effects occur within seconds after smoking marijuana, 
while the onset of effects after oral administration is 30-60 min. 
After a single moderate smoked dose, most mental and behavioral effects 
are measurable for approximately 4 to 6 hours (Hollister 1986, 1988). 
Venous blood levels of delta\9\-THC or other cannabinoids correlate 
poorly with intensity of effects and character of intoxication (Agurell 
et al. 1986; Barnett et al. 1985; Huestis et al. 1992a). There does not 
appear to be a ``hangover'' syndrome following acute administration of 
marijuana containing 2.1% delta\9\-THC (Chait, 1985).
    We agree with the petitioner that clinical studies do not 
demonstrate tolerance to the ``high'' from marijuana. This may be 
related to recent electrophysiological data showing that the ability of 
THC to increase neuronal firing in the ventral tegmental area (a region 
known to play a critical role in drug reinforcement and reward) is not 
reduced following chronic administration of the drug (Wu and French, 
2000). On the other hand, tolerance can develop in humans to marijuana-
induced cardiovascular and autonomic changes, decreased intraocular 
pressure, sleep and sleep EEG, mood and certain behavioral changes 
(Jones et al., 1981).
    Repeated use of many drugs leads to the normal physiological 
adaptations of tolerance and dependence and is not a phenomenon unique 
to drugs of abuse. Down-regulation of cannabinoid receptors has been 
suggested as the mechanism underlying tolerance to the effects of 
marijuana (Rodriguez de Fonseca et al., 1994, Oviedo et al., 1993). By 
pharmacological definition, tolerance does not indicate the physical 
dependence liability of a drug.
    Physical dependence is a condition resulting from the repeated 
consumption of certain drugs. Discontinuation of the drug results in 
withdrawal signs and symptoms known as withdrawal or abstinence 
syndrome. It is believed that the withdrawal syndrome probably reflects 
a rebound of certain physiological effects that were altered by the 
repeated administration of the drug. These pharmacological events of 
physical dependence and withdrawal are not associated uniquely with 
drugs of abuse. Many medications such as antidepressants, beta-blockers 
and centrally acting antihypertensive drugs that are not associated 
with addiction can produce these effects after abrupt discontinuation.
    Some authors describe a marijuana withdrawal syndrome consisting of 
restlessness, irritability, mild agitation, insomnia, sleep EEG 
disturbances, nausea and cramping that resolves in days (Haney et al., 
1999). This syndrome is mild compared to classical alcohol and 
barbiturate withdrawal phenomena, which may include agitation, 
paranoia, and seizures. Marijuana withdrawal syndrome has more 
frequently been reported in adolescents who were admitted for substance 
abuse treatment or under research conditions upon discontinuation of 
daily administration.
    According to the American Psychiatric Association, Diagnostic and 
Statistical Manual (DSM-IV-TR\TM\, 2000), the distinction between 
occasional use of cannabis and cannnabis dependence or abuse can be 
difficult to make because social, behavioral, or psychological problems 
may be difficult to attribute to the substance, especially in the 
context of use of other substances. Denial of heavy use is common, and 
people appear to seek treatment for cannabis dependence or abuse less 
often than for other types of substance-related disorders.
    Although pronounced withdrawal symptoms can be provoked from the 
administration of a cannabinoid antagonist in animals who had received 
chronic THC administration, there is no overt withdrawal syndrome 
behaviorally in animals under conditions of natural discontinuation 
following chronic THC administration.

[[Page 20044]]

This may be the result of slow release of cannabinoids from adipose 
storage, as well as the presence of the major metabolite, 11-OH-
delta\9\-THC, which is also psychoactive.

Cognitive Effects

    Acute administration of smoked marijuana impairs performance on 
tests of learning, associative processes, and psychomotor behavior 
(Block et al., 1992). These data demonstrate that the short-term 
effects of marijuana can interfere significantly with an individual's 
ability to learn in the classroom or to operate motor vehicles. 
Administration of 290 ug/kg delta\9\-THC in a smoked marijuana 
cigarette by human volunteers impaired perceptual motor speed and 
accuracy, two skills that are critical to driving ability (Kurzthaler 
et al., 1999). Similarly, administration of 3.95% delta\9\-THC in a 
smoked marijuana cigarette increased dysequilibrium measures as well as 
the latency in a task of simulated vehicle braking at a rate comparable 
to an increase in stopping distance of 5 feet at 60 mph (Liguori et 
al., 1998).
    The effects of marijuana may not resolve fully until at least a day 
after the acute psychoactive effects have subsided. A study at the 
National Institute on Drug Abuse (NIDA) showed residual impairment on 
memory tasks 24 hours after volunteer subjects had smoked 0, 1, or 2 
marijuana cigarettes containing 2.57% delta\9\-THC on two occasions the 
previous day (Heishman et al., 1990). However, later studies at NIDA 
showed that there were no residual alterations in subjective or 
performance measures the day after subjects were exposed to 1.8%, or 
3.6% smoked delta\9\-THC, indicating that the residual effects of 
smoking a single marijuana cigarette are minimal (Fant et al., 1998). A 
John Hopkins study examined marijuana's effects on cognition on 1,318 
participants over a 15-year period and reported there were no 
significant differences in cognitive decline between heavy users, light 
users, and nonusers of cannabis, nor any male-female differences. The 
authors concluded that ``these results * * * seem to provide strong 
evidence of the absence of a long-term residual effect of cannabis use 
on cognition.'' (Lyketsos et al., 1999).
    Age of first use may be a critical factor in persistent impairment 
resulting from chronic marijuana use. Individuals with a history of 
marijuana-only use that began before the age of 16 were found to 
perform more poorly on a visual scanning task measuring attention than 
individuals who started using marijuana after that age (Ehrenreich et 
al., 1999). However, the majority of early-onset marijuana users do not 
go on to become heavy users of marijuana, and those that do tend to 
associate with delinquent social groups (Kandel and Chen, 2000).
    An individual's drug history may play a role in the response that 
person has to marijuana. Frequent marijuana users (greater than 100 
times) were better able to identify a drug effect from low dose 
delta\9\-THC than infrequent users (less than 10 times) and were less 
likely to experience sedative effects from the drug (Kirk and deWit, 
1999). This difference in experiential history may account for data 
showing that reaction times are not altered by acute administration of 
marijuana in long term marijuana users (Block and Wittenborn, 1985), 
suggesting that behavioral adaptation or tolerance can occur to the 
acute effects of the drug in the absence of evidence for dependence.
    The impact of in utero marijuana exposure on a series of cognitive 
tasks had been studied in children at different stages of development. 
Differences in several cognitive domains distinguished the 4-year-old 
children of heavy marijuana users. In particular, memory and verbal 
measures were negatively associated with maternal marijuana use (Fried 
and Watkinson, 1987). Maternal marijuana use was predictive of poorer 
performance on abstract/visual reasoning tasks, although it was not 
associated with an overall lowered IQ in 3-year old children (Griffith 
et al., 1994). At 6 years of age, prenatal marijuana history was 
associated with an increase in omission errors on a vigilance task, 
possibly reflecting a deficit in sustained attention, was noted (Fried 
et al., 1992). Recently, it had been speculated that prenatal exposure 
may affect certain behaviors and cognitive abilities that fall under 
the construct termed executive function, that is, not associated with 
measures of global intelligence. It was postulated that when tests 
evaluate novel problem-solving abilities as contrasted to knowledge, 
there is an association between executive function and intelligence. In 
a recent study (Fried et al., 1998), the effect of prenatal exposure in 
9-12 year old children was analyzed, and similarly to what was shown in 
other age groups, in utero marijuana exposure was negatively associated 
with executive function tasks that require impulse control, visual 
analysis and hypothesis testing and it was not associated with global 
intelligence.

Cardiovascular and Autonomic Effects

    Single smoked or oral doses of delta\9\-THC ingestion produce 
tachycardia and unchanged or increased blood pressure (Capriotti et 
al., 1988, Benowitz and Jones, 1975). However, prolonged delta\9\-THC 
ingestion produces significant heart rate slowing and blood pressure 
lowering (Benowitz and Jones, 1975). Both plant-derived cannabinoids 
and the endogenous ligands have been shown to elicit hypotension and 
bradycardia via activation of peripherally located CB1 
receptors (Wagner et al., 1998). The mechanism of these effects were 
suggested in that study to include presynaptic CB1 receptor 
mediated inhibition of norepinephrine release from peripheral 
sympathetic nerve terminals, with the possibility of additional direct 
vasodilation via activation of vascular cannabinoid receptors.
    Impaired circulatory responses to standing, exercise, Valsalva 
maneuver, and cold pressor testing following THC administration suggest 
a state of sympathetic insufficiency. Tolerance developed to the 
orthostatic hypotension, possibly related to plasma volume expansion, 
but did not develop to the supine hypotensive effects. During chronic 
marijuana ingestion, nearly complete tolerance was shown to have 
developed to the tachycardia and psychological effects when subjects 
were challenged with smoked marijuana. Electrocardiographic changes 
were minimal despite the large cumulative dose of THC. (Benowitz and 
Jones, 1975)
    Cardiovascular effects of smoked or oral marijuana have not been 
shown to result in any health problems in healthy and relatively young 
users. However, marijuana smoking by older patients, particularly those 
with some degree of coronary artery or cerebrovascular disease, is 
postulated to pose greater risks, because of the resulting increased 
cardiac work, increased catecholamines, carboxyhemoglobin, and postural 
hypotension (Benowitz and Jones 1981; Hollister 1988).
    As a comparison, the cardiovascular risks associated with use of 
cocaine are quite serious, including cardiac arrhythmias, myocardial 
ischemia, myocarditis, aortic dissection, cerebral ischemia, stroke and 
seizures.

Respiratory Effects

    Transient bronchodilation is the most typical effect following 
acute exposure to marijuana. The petitioner is correct that marijuana 
does not suppress respiration in a manner that leads to death. With 
long-term use of marijuana, there can be an increased frequency of 
pulmonary illness from chronic bronchitis and pharyngitis. Large-airway 
obstruction, as evident on pulmonary function tests, can also occur 
with

[[Page 20045]]

chronic marijuana smoking, as can cellular inflammatory 
histopathological abnormalities in bronchial epithelium (Adams and 
Martin 1996; Hollister 1986).
    The low incidence of carcinogenicity may be related to the fact 
that intoxication from marijuana does not require large amounts of 
smoked material. This may be especially true today since marijuana has 
been reported to be more potent now than a generation ago and 
individuals typically titrate their drug consumption to consistent 
levels of intoxication. Several cases of lung cancer in young marijuana 
users with no history of tobacco smoking or other significant risk 
factors have been reported (Fung et al. 1999). However, a recent study 
(Zhang et al., 1999) has suggested that marijuana use may dose-
dependently interact with mutagenic sensitivity, cigarette smoking and 
alcohol use to increase the risk of head and neck cancer. The 
association of marijuana use with carcinomas remains controversial.

Endocrine System Effects

    In male human volunteers, neither smoked THC (18 mg/marijuana 
cigarette) nor oral THC (10 mg t.i.d. for 3 days and on the morning of 
the fourth day) altered plasma prolactin, ACTH, cortisol, luteinizing 
hormone or testosterone levels (Dax et al., 1989). Reductions in male 
fertility by marijuana are reversible and only seen in animals at 
concentrations higher than those found in chronic marijuana users.
    Relatively little research has been performed on the effects of 
experimentally administered marijuana on human female endocrine and 
reproductive system function. Although suppressed ovulation and other 
ovulatory cycle changes occur in nonhuman primates, a study of human 
females smoking marijuana in a research hospital setting did not find 
hormone or menstrual cycle changes like those in monkeys that had been 
given delta\9\-THC (Mendelson et al., 1984a).
    THC reduces binding of the corticosteroid dexamethasone in 
hippocampal tissue from adrenalectomized rats, suggesting a direct 
interaction with the glucocorticoid receptor. Chronic THC 
administration also reduced the number of glucocorticoid receptors. 
Acute THC releases corti-costerone, but tolerance developed with 
chronic THC administration. (Eldridge et al., 1991)

Immune System Effects

    Immune functions can be enhanced or diminished by cannabinoids, 
dependent on experimental conditions, but the effects of endogenous 
cannabinoids on the immune system are not yet known. The concentrations 
of THC that are necessary for psychoactivity are lower than those that 
alter immune responses.
    A study presented by Abrams and coworkers at the University of 
California, San Francisco at the XIII International AIDS Conference 
investigated the effect of marijuana on immunological functioning in 62 
AIDS patients who were taking protease inhibitors. Subjects received 
one of three treatments, three times a day: Smoked marijuana cigarette 
containing 3.95% THC; oral tablet containing THC (2.5 mg oral 
dronabinol); or oral placebo. There were no changes in HIV RNA levels 
between groups, demonstrating no short-term adverse virologic effects 
from using cannabinoids. Additionally, those individuals in the 
cannabinoid groups gained more weight than those in the placebo group 
(3.51 kg from smoked marijuana, 3.18 kg from dronabinol, 1.30 kg from 
placebo) (7/13/00, Durban, South Africa).
3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance
    This section discusses the chemistry, human pharmacokinetics, and 
medical uses of marijuana.

Chemistry

    According to the DEA, three forms of cannabis (that is, Cannabis 
sativa L. and other species) are currently marketed illicitly in the 
U.S.A. These cannabis derivatives include marijuana, hashish and 
hashish oil.
    Each of these forms contains a complex mixture of chemicals. Among 
these components the twenty-one carbon terpenes found in the plant as 
well as their carboxylic acids, analogues, and transformation products 
are known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam, 
1973). The cannabinoids appear to be unique to marijuana and most of 
the naturally-occurring have been identified. Among the cannabinoids, 
delta\9\-tetrahydrocannabinol (delta\9\-THC, alternate name delta\1\-
THC) and delta-8-tetrahydrocannabinol (delta\8\-THC, alternate name 
delta\6\-THC) are the only compounds in the plant, which show all of 
the psychoactive effects of marijuana. Because delta\9\-THC is more 
abundant than delta\8\-THC, the activity of marijuana is largely 
attributed to the former, which is considered the main psychoactive 
cannabinoid in cannabis. Delta8-THC is found only in few 
varieties of the plant (Hively et al., 1966). Other cannabinoids, such 
as cannabidiol (CBD) and cannabinol (CBN), has been characterized. CBD 
is not considered to have cannabinol-like psychoactivity, but is 
thought to have significant anticonvulsant, sedative, and anxiolytic 
activity (Adams and Martin, 1996; Agurell et al., 1984, 1986; 
Hollister, 1986).
    Marijuana is a mixture of the dried flowering tops and leaves from 
the plant (Agurell et al. 1984; Graham 1976; Mechoulam 1973) and is 
variable in content and potency (Agurell et al. 1986; Graham 1976; 
Mechoulam 1973). Marijuana is usually smoked in the form of rolled 
cigarettes. The other cannabis forms are also smoked. Potency of 
marijuana, as indicated by cannabinoid content, has been reported to 
average from as low as one to two percent to as high as 17 percent.
    Delta9-THC is an optically active resinous substance, 
insoluble in water and extremely lipid soluble. Chemically is known as 
(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-
[b,d]pyran-1-ol or (-)-delta\9\-(trans)-tetrahydrocannabinol. The 
pharmacological activity of delta\9\-THC is stereospecific; the (-)-
trans isomer is 6-100 times more potent than the (+)-trans isomer 
(Dewey et al., 1984).
    The concentration of delta\9\-THC and other cannabinoids in 
marijuana varies greatly depending on growing conditions, parts of the 
plant collected (flowers, leaves stems, etc), plant genetics, and 
processing after harvest (Adams and Martin , 1996; Agurell et al., 
1984; Mechoulam, 1973). Thus, there are many variables that can 
influence the strength, quality and purity of marijuana as a botanical 
substance. In the usual mixture of leaves and stems distributed as 
marijuana, the concentration of delta\9\-THC ranges from 0.3 to 4.0 
percent by weight. However, specially grown and selected marijuana can 
contain 15 percent or even more delta\9\-THC. Thus, a one-gram 
marijuana cigarette might contain as little as 3 milligrams or as much 
as 150 milligrams or more of delta\9\-THC among several other 
cannabinoids. As a consequence, the clinical pharmacology of pure 
delta\9\-THC may not always be expected to have the same clinical 
pharmacology of smoked marijuana containing the same amount of 
delta\9\-THC (Harvey, 1985). Also, the lack of consistency of 
concentration of delta\9\-THC in botanical marijuana from diverse 
sources makes the interpretation of clinical data very difficult. If 
marijuana is to be investigated more widely for medical use, 
information and data regarding the chemistry, manufacturing and 
specifications of marijuana must be developed. 21 CFR 314.50(d)(1)

[[Page 20046]]

describes the data and information that should be included in the 
chemistry, manufacturing and controls section of a new drug application 
(NDA) to be reviewed by FDA.
    Hashish consists of the cannabinoid-rich resinous material of the 
cannabis plant, which is dried and compressed into a variety of forms 
(balls, cakes etc.). Pieces are then broken off, placed into pipes and 
smoked. Cannabinoid content in hashish has recently been reported by 
DEA to average 6 percent.
    Hash oil is produced by extracting the cannabinoids from plant 
material with a solvent. Color and odor of the extract vary, depending 
on the type of solvent used. Hash oil is a viscous brown or amber-
colored liquid that contains approximately 15 percent cannabinoids. One 
or two drops of the liquid placed on a cigarette purportedly produce 
the equivalent of a single marijuana cigarette.

Human Pharmacokinetics

    Marijuana is generally smoked as a cigarette (weighing between 0.5 
and 1.0 gram), or in a pipe. It can also be taken orally in foods or as 
extracts of plant material in ethanol or other solvents. Pure 
preparations of delta9-THC and other cannabinoids can be 
administered by mouth, rectal suppository, intravenous injection, or 
smoked.
    The absorption, metabolism, and pharmacokinetic profile of 
delta9-THC (and other cannabinoids) in marijuana or other 
drug products containing delta9-THC are determined by route 
of administration and formulation (Adams and Martin 1996; Agurell et 
al. 1984, 1986). When marijuana is administered by smoking, 
delta9-THC in the form of an aerosol in the inhaled smoke is 
absorbed within seconds. The delta9-THC is delivered to the 
brain rapidly and efficiently as would be expected of a very lipid-
soluble drug. The delta9-THC bioavailability from smoked 
marijuana, i.e., the actual absorbed dose as measured in blood, varies 
greatly among individuals. Bioavailability can range from one percent 
to 24 percent with the fraction absorbed rarely exceeding 10 to 20 
percent of the delta9-THC in a marijuana cigarette or pipe 
(Agurell et al. 1986; Hollister 1988a). This relatively low and quite 
variable bioavailability results from significant loss of 
delta9-THC in side-stream smoke, from variation in 
individual smoking behaviors, from cannabinoid pyrolysis, from 
incomplete absorption of inhaled smoke, and from metabolism in the 
lungs. A smoker's experience is likely an important determinant of the 
dose that is actually absorbed (Herning et al. 1986; Johansson et al. 
1989). Venous blood levels of delta9-THC or other 
cannabinoids correlate poorly with intensity of effects and character 
of intoxication (Agurell et al. 1986; Barnett et al. 1985; Huestis et 
al. 1992a).
    After smoking, venous levels of delta9-THC decline 
precipitously within minutes, and within an hour are about 5 to 10 
percent of the peak level (Agurell et al., 1986, Huestis et al., 1992a, 
1992b). Plasma clearance of delta9-THC is approximately 950 
mL/min or greater, thus approximating hepatic blood flow. The rapid 
disappearance of delta9-THC from blood is largely due to 
redistribution to other tissues in the body, rather than to metabolism 
(Agurell et al., 1984, 1986). Metabolism in most tissues is relatively 
slow or absent. Slow release of delta9-THC and other 
cannabinoids from tissues and subsequent metabolism results in a long 
elimination half-life. The terminal half-life of delta9-THC 
is estimated to range from approximately 20 hours to as long as 10 to 
13 days, though reported estimates vary as expected with any slowly 
cleared substance and the use of assays of variable sensitivities.
    In contrast, following an oral dose of delta9-THC or 
marijuana, maximum delta9-THC and other cannabinoid blood 
levels are attained after 2 to 3 hours (Adams and Martin 1996; Agurell 
et al. 1984, 1986). Oral bioavailability of delta9-THC, 
whether pure or in marijuana, is low and extremely variable, ranging 
between 5 and 20 percent (Agurell et al. 1984, 1986). There is inter-
and intra-subject variability, even when repeatedly dosed under 
controlled and ideal conditions. The low and variable oral 
bioavailability of delta9-THC is a consequence of its first-
pass hepatic elimination from blood and erratic absorption from stomach 
and bowel. Because peak effects are slow in onset, typically one or two 
hours after an oral dose, and variable in intensity, it is more 
difficult for a user to titrate the oral delta9-THC dose 
than with marijuana smoking. When smoked, the active metabolite, 11-
hydroxy-delta9-THC, probably contributes little to the 
effects since relatively little is formed, but after oral 
administration, metabolite levels produced may exceed that of 
delta9-THC and thus contribute greatly to the 
pharmacological effects of oral delta9-THC or marijuana. 
Delta9-THC is metabolized via microsomal hydroxylation to 
more than 80, active and inactive, metabolites (Lemberger et al., 1970, 
Lemberger et al., 1972a, 1972b) of which the primary active metabolite 
was 11-OH-delta9-THC. This metabolite is approximately 
equipotent to delta9-THC in producing marijuana-like 
subjective effects (Agurell et al., 1986, Lemberger and Rubin, 1975). 
Following oral administration of radioactive-labeled delta9-
THC, it has been confirmed that delta9-THC plasma levels 
attained by the oral route are low relative to those levels after 
smoking or intravenous administration. The half-life of 
delta9-THC has been determined to be 23-28 hours in heavy 
marijuana users, but 60-70 hours in naive users (Lemberger et al., 
1970).
    Characterization of the pharmacokinetics of delta\9\-THC and other 
cannabinoids from smoked marijuana is difficult (Agurell et al., 1986, 
Herning et al., 1986, Heustis et al., 1992a) in part because a 
subject's smoking behavior during an experiment cannot be easily 
controlled or quantified by the researcher. An experienced marijuana 
smoker can titrate and regulate the dose to obtain the desired acute 
psychological effects and to avoid overdose and/or minimize undesired 
effects. Each puff delivers a discrete dose of delta\9\-THC to the 
body. Puff and inhalation volume changes with phase of smoking, tending 
to be highest at the beginning and lowest at the end of smoking a 
cigarette. Some studies found frequent users to have higher puff 
volumes than less frequent marijuana users. During smoking, as the 
cigarette length shortens, the concentration of delta\9\-THC in the 
remaining marijuana increases; thus, each successive puff contains an 
increasing concentration of delta\9\-THC.
    Cannabinoid metabolism is extensive. There are at least 80 probable 
biologically inactive, but not completely studied, metabolites formed 
from delta\9\-THC (Agurell et al., 1986; Hollister, 1988a). In addition 
to the primary active metabolite, 11-hydroxy-delta\9\-THC, some 
inactive carboxy metabolites have terminal half-lives of 50 hours to 6 
days or more. The latter substances serve as long term markers of 
earlier marijuana use in urine tests. Most of the absorbed delta\9\-THC 
dose is eliminated in feces, and about 33 percent in urine. Delta\9\-
THC enters enterohepatic circulation and undergoes hydroxylation and 
oxidation to 11-nor-9-carboxy-delta\9\-THC. The glucuronide is excreted 
as the major urine metabolite along with about 18 nonconjugated 
metabolites. Frequent and infrequent marijuana users are similar in the 
way they metabolize delta\9\-THC (Agurell et al., 1986).

Medical Uses for Marijuana

    FDA has not approved a new drug application for marijuana, although 
there are several INDs currently active. There is suggestive evidence 
that

[[Page 20047]]

marijuana may have beneficial therapeutic effects in relieving 
spasticity associated with multiple sclerosis, as an analgesic, as an 
antiemetic, as an appetite stimulant and as a bronchodilator, but there 
is no data from controlled clinical trials to support a new drug 
application for any of these indications. Data of the risks and 
potential benefits of using marijuana for these various indications 
must be developed to determine whether botanical marijuana, or any 
cannabinoid in particular, has a therapeutic role.
    In February 1997, a 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'' 
(NIH, 1997). In addition, in March 1999, the Institute of Medicine 
(IOM) issued a detailed report that supports the absolute need for 
evidence-based research into the effects of marijuana and cannabinoid 
components of marijuana, for patients with specific disease conditions. 
The IOM report also 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 (Institute of Medicine, 1999). Additionally, State-
level public initiatives, including referenda in support of the medical 
use of marijuana have generated interest in the medical community for 
high quality clinical investigation and comprehensive safety and 
effectiveness data.
    The Department of Health and Human Services (DHHS) is committed to 
providing ``research-grade marijuana for studies that are the most 
likely to yield usable, essential data'' (DHHS, 1999). The opportunity 
for scientists to conduct clinical research with botanical marijuana 
has increased due to changes in the process for obtaining botanical 
marijuana from the National Institute on Drug Abuse, the only legal 
source of the drug for research. Studies published in the current 
medical literature demonstrate that clinical research with marijuana is 
being conducted in the US under FDA-authorized Investigational New Drug 
applications. In May 1999, DHHS provided guidance on the procedures for 
providing research-grade marijuana to scientists who intend to study 
marijuana in scientifically valid investigations and well-controlled 
clinical trials (DHHS, 1999). This action was prompted by the 
increasing interest in determining through scientifically valid 
investigations whether cannabinoids have medical use.
4. Its History and Current Pattern of Abuse
    To assess drug abuse patterns and trends, data from different 
sources such as National Household Survey on Drug Abuse (NHSDA), 
Monitoring the Future (MTF), Drug Abuse Warning Network (DAWN), and 
Treatment Episode Data Set (TEDS) have been analyzed. These indicators 
of marijuana use in the United States are described below:

National Household Survey on Drug Abuse

    The National Household Survey on Drug Abuse (NHSDA, 1999) is 
conducted by the Department of Health and Human Service's Substance 
Abuse and Mental Health Services Administration (SAMHSA) annually. This 
survey has been the primary source of estimates of the prevalence and 
incidence of alcohol, tobacco and illicit drug use in the US. It is 
important to note that this survey identifies whether an individual 
used a drug during a certain period, but not the amount of the drug 
used on each occasion. The survey is based on a nationally 
representative sample of the civilian, non-institutionalized population 
12 years of age and older. Persons excluded from the survey include 
homeless people who do not use shelters, active military personnel, and 
residents of institutional group quarters, such as jails and hospitals. 
In 1999, 66,706 individuals were interviewed.
    According to the 1999 NHSDA, illicit drug use involved 
approximately 14.8 million Americans (6.7% of the US population) on a 
monthly basis. The most frequently used illicit drug was marijuana, 
with 11.2 million Americans (5.1% of the US population) using it 
monthly. The 1999 NHSDA no longer provides data on the weekly or daily 
use of any drug, so these statistics are unavailable for marijuana. The 
NHSDA estimated that 76.4 million Americans (34.6% of the population) 
have tried marijuana at least once during their lifetime. Thus, 14.7% 
of those who try marijuana go on to use it monthly. NHSDA data from 
1999 show that 57% of illicit drug users only use marijuana on a 
monthly basis, which corresponds to 8.44 million persons (3.8% of the 
US population). However, there are no data available on marijuana-only 
use as a percent of use of any drug.
    An estimated 2.3 million persons of all ages used marijuana for the 
first time in 1998, of whom 1.6 million were between the ages of 12-17. 
(Information on when people first used a substance is collected on a 
retrospective basis, so this information is always one year behind 
information on current use.) This represents a slight reduction in new 
marijuana users from 1997, when the rate was 2.6 million people of all 
ages and 1.8 million for those 12-17 years old. Trends for marijuana 
use were similar to the trends for any illicit use. There were no 
significant changes between 1998 and 1999 for any of the four age 
groups, but an increasing trend since 1997 among young adults age 18-25 
years (12.8 % in 1997, 13.8 % in 1998, and 16.4 % in 1999) and a 
decreasing trend since 1997 for youths age 12-17 years (9.4 % in 1997, 
8.3 % in 1998, and 7.0 % in 1999).

Monitoring the Future

    Monitoring the Future (MTF, 1999) is a national survey that tracks 
drug use trends among American adolescents. The MTF has surveyed 8th, 
10th and 12th graders every spring in randomly selected U.S. schools 
since 1975 for 12th graders and since 1991 for 8th and 10th graders. 
This survey is conducted by the Institute for Social Research at the 
University of Michigan under a grant from NIDA. The 1999 sample sizes 
were 17,300, 13,900, and 14,100 in 8th, 10th, and 12th grades, 
respectively. In all, about 45,000 students in 433 schools 
participated. Because multiple questionnaire forms are administered at 
each grade level, and because not all questions are contained in all 
forms, the numbers of cases upon which a particular statistic are based 
can be less than the total sample.
    Comparisons between the MTF and students sampled in the NHSDA 
(described above) have generally shown NHSDA prevalence to be lower 
than MFT estimates, in which the largest difference occurred with 8th 
graders. The MTF survey showed the use of illegal drugs by adolescents 
leveled off in 1997 and then declined somewhat for most drugs in 1998. 
Also, the 1998-year survey showed that for the first time since 1991 an 
increase in the percentage of 8th graders who said marijuana is a risk 
to their health.
    Illicit drug use among teens remained steady in 1999 in all three 
grades, as did the use of a number of important specific drugs such as 
marijuana, amphetamines, hallucinogens taken as a class, tranquilizers, 
heroin, and alcohol. Marijuana is the most widely used illicit drug. 
For 1999, the annual prevalence rates in grades 8, 10, and 12,

[[Page 20048]]

respectively, are 17%, 32%, and 38%. Current monthly prevalence rates 
are 9.7%, 19.4% and 23.1%. (See Table 1), whereas current daily 
prevalence rates (defined as the proportion using it on 20 or more 
occasions in the prior thirty days) are 1.4%, 3.8%, and 6.0%.

   Table 1.--Trends in Annual and Monthly Prevalence of Use of Various
              Drugs for Eighth, Tenth, and Twelfth Graders
                        [Entries are precentages]
------------------------------------------------------------------------
                                       Annual               30-Day
             Grade             -----------------------------------------
                                 1997   1998   1999   1997   1998   1999
------------------------------------------------------------------------
                          Any illicit drug (a)
------------------------------------------------------------------------
8th...........................   22.1   21.0   20.5   12.9   12.1   12.2
10th..........................   38.5   35.0   35.9   23.0   21.5   22.1
12th..........................   42.4   41.4   42.1   26.2   25.6   25.9
------------------------------------------------------------------------
                Any illicit drug other than cannabis (a)
------------------------------------------------------------------------
8th...........................   11.8   11.0   10.5    6.0    5.5    5.5
10th..........................   18.2   16.6   16.7    8.8    8.6    8.6
12th..........................   20.7   20.2   20.7   10.7   10.7   10.4
------------------------------------------------------------------------
                            Marijuana/hashish
------------------------------------------------------------------------
8th...........................   17.7   16.9   16.5   10.2    9.7    9.7
10th..........................   34.8   31.1   32.1   20.5   18.7   19.4
12th..........................   38.5   37.5   37.8   23.7   22.8   23.1
------------------------------------------------------------------------
                                 Cocaine
------------------------------------------------------------------------
8th...........................    2.8    3.1    2.7    1.1    1.4    1.3
10th..........................    4.7    4.7    4.9    2.0    2.1    1.8
12th..........................    5.5    5.7    6.2    2.3    2.4    2.6
------------------------------------------------------------------------
                               Heroin (b)
------------------------------------------------------------------------
8th...........................    1.3    1.3    1.4    0.6    0.6    0.6
10th..........................    1.4    1.4    1.4    0.6    0.7    0.7
12th..........................    1.2    1.0    1.1    0.5    0.5   0.5
------------------------------------------------------------------------
Source. The Monitoring the Future Study, the University of Michigan.

    a. For 12th graders only: Use of ``any illicit drug'' includes any 
use of marijuana, LSD, other hallucinogens, crack, other cocaine, or 
heroin, or any use of other opiates, stimulants, barbiturates, or 
tranquilizers not under a doctor's orders. For 8th and 10th graders: 
The use of other opiates and barbiturates has been excluded, because 
these younger respondents appear to over-report use (perhaps because 
they include the use of nonprescription drugs in their answers).
    b. In 1995, the heroin question was changed in three of six forms 
for 12th graders and in two forms for 8th and 10th graders. Separate 
questions were asked for use with injection and without injection. Data 
presented here represents the combined data from all forms. In 1996, 
the heroin question was changed in the remaining 8th and 10th grade 
forms.

Drug Abuse Warning Network (DAWN)

    The Drug Abuse Warning Network (DAWN, 1998) is a national 
probability survey of hospitals with emergency departments (EDs) 
designed to obtain information on ED episodes that are induced by or 
related to the use of an illegal drug or the non-medical use of a legal 
drug. The DAWN system provides information on the health consequences 
of drug use in the United States as manifested by drug-related visits 
to emergency departments (ED episodes). DAWN captures the non-medical 
use of a substance either for psychological effects, dependence, or 
suicide attempt. The ED data come from a representative sample of 
hospital emergency department's which are weighted to produce national 
estimates. As stated in DAWN methodology, ``the terms 'ED drug abuse 
episode' or 'ED episode' refer to any ED visit that was induced by or 
related to drug abuse. Similarly, the terms 'ED drug mention' or 'ED 
mention' refer to a substance that was mentioned in a drug abuse 
episode. Up to 4 substances can be reported for each ED episode. Thus, 
the number of ED mentions will always equal or exceed the number of ED 
episodes.''
    Many factors can influence the estimates of ED visits, including 
trends in the ED usage in general. Some drug users may have visited EDs 
for a variety of reasons, some of which may have been life threatening, 
whereas others may have sought care at the ED for detoxification 
because they needed certification before entering treatment. It is 
important to note that the variable ``Motive'' applies to the entire 
episode and since more than one drug can be mentioned per episode, it 
may not apply to the specific drug for which the tables have been 
created. DAWN data do not distinguish the drug responsible for the ED 
visit from others used concomitantly. The DAWN report itself states, 
``Since marijuana/hashish is frequently present in combination with 
other drugs, the reason for the ED contact may be more relevant to the 
other drug(s) involved in the episode.''
    In 1999, there were an estimated 554,932 drug-related ED episodes 
and 1,015,206 ED drug mentions from these drug-related episodes. 
Nationally, the number of ED episodes and mentions remained relatively 
stable from 1998 to 1999. The 4 drugs mentioned most frequently in ED 
reports--alcohol-in-combination (196,277 mentions), cocaine (168,763), 
marijuana/hashish (87,150), and heroin/morphine (84,409)--were 
statistically unchanged from 1998 to 1999. Marijuana/hashish mentions 
represented 16% of all drug-related episodes in 1999. For adolescent 
patients age 12-17, there was no statistical change from 1998 to 1999 
in drug use for any drug category (Table 2). There was no a 
statistically significant change in the number of marijuana/hashish 
mentions, heroin/morphine of cocaine from 1998 to 1999.

 Table 2.--Estimated Number of Emergency Department Drug Episodes, Drug
  Mentions and Mentions for Selected Drugs for Total Coterminous US by
                           year for 1997-1999
------------------------------------------------------------------------
                                           1997      1998        1999
------------------------------------------------------------------------
Drug episodes..........................   527,058   542,544      554,932
Drug mentions..........................   943,937   982,856    1,015,206
Cocaine................................   161,087   172,014      168,763
Heroin/Morphine........................    72,010    77,645       84,409
Marijuana/Hashish......................    64,744    76,870      87,150
------------------------------------------------------------------------
Source: Office of applied studies, SAMHSA, Drug Abuse Warning Network,
  1999 (03/2000 update). Note: These estimates are based on a
  representative sample of non-federal, short-stay hospitals with 24-
  hour emergency departments in the U.S.

    There were no statistically significant increases in marijuana/
hashish mentions on the basis of age, gender, or race/ethnicity 
subgroups between 1998 and 1999, although a 19% increase in marijuana/
hashish mentions (from 22,907 to 27,272) among young adults age 18 to 
25 was observed.
    Approximately 15 percent of the emergency department marijuana/
hashish mentions involved patients in the 6-17 years of age, whereas 
this age group only accounts for less than 1 percent of the emergency 
department heroin/morphine and approximately 2 percent of the cocaine 
emergency department mentions. Most of the emergency department heroin/
morphine and cocaine mentions involved subjects in the 26-44 years of 
age range.
    Marijuana/hashish is likely to be mentioned in combination with 
other substances, particularly with alcohol and cocaine. Marijuana use 
as a single drug accounted for approximately 22% of the marijuana 
episodes. Single use of cocaine and heroin accounted for 29% and 47% of 
the cocaine and heroine episodes respectively.
    The petitioner asserts that ``common household painkillers'' and 
benzodiazepines produce more ED visits than marijuana and that 
marijuana users are no more likely to be seen in EDs

[[Page 20049]]

than other chronic drug users. DAWN data do not confirm the 
petitioner's assertions. For 1999, the estimated rate of mentions of 
selected drugs per 100,000 population is 69.4 for cocaine, 35.8 for 
marijuana/hashish, 34.7 for heroin/morphine, 17.5 for alprazolam/
diazepam/lorazepam, and 16.9 for aspirin/acetaminophen. The estimated 
rate of mentions of marijuana/hashish per 100,000 population is similar 
to that of heroin/morphine, but approximately twice that of aspirin/
acetaminophen and that of alprazolam/diazepam/ lorazepam. However, 
marijuana estimated rate of mentions/100,000 population is 
approximately half that of cocaine.
    These drugs are easily distinguished by the motivation for their 
use. In 1999, marijuana/hashish mentions were related to episodes in 
which the motive for drug intake was primarily dependence (34.2%) 
followed by recreational use (28%), suicide (11.5%) and other psychic 
effects (8.1%). DAWN defines ``psychic effects'' as a conscious action 
to use a drug to improve or enhance any physical, emotional, or social 
situation or condition. The use of a drug for experimentation or to 
enhance a social situation, as well as the use of drugs to enhance or 
improve any mental, emotional, or physical state, is reported to DAWN 
under this category. Examples of the latter include anxiety, stay 
awake, help to study, weight control, reduce pain and to induce sleep. 
A different pattern is observed for tranquilizers (alprazolam/diazepam/
lorazepam) and aspirin/acetamipnophen. Alprazolam/diazepam/lorazepam 
mentions were primarily related to episodes where the motive for drug 
intake was primarily suicide (approximately 58%), followed by 
dependence (approximately 17%), other psychic effects (approximately 
11%), and recreational use (approximately 5%). For the use of aspirin/
acetaminophen the primary motive of the episode was suicide (80%), 
other psychic effects (9%) and recreational use (2%).
    DAWN also collects information on drug-related deaths from selected 
medical examiner offices from more than 40 metropolitan areas. In 1997 
and 1998, there were 678 and 595 marijuana-related death mentions, 
representing 7.1 and 5.9 percent of the total drug abuse deaths for 
each year respectively. Medical examiner data also showed that in the 
majority of the mentions, marijuana was used concomitantly with 
cocaine, heroin and alcohol.

Treatment Episode Data Set

    The Treatment Episode Data Set (TEDS, 1998) system is part of 
SAMHSA's Drug and Alcohol Services Information System (Office of 
Applied Science, SAMHSA). TEDS comprises data on treatment admissions 
that are routinely collected by States in monitoring their substance 
abuse treatment systems. The TEDS report provides information on the 
demographic and substance use characteristics of the 1.5 million annual 
admissions to treatment for abuse of alcohol and drugs in facilities 
that report to individual State administrative data systems. It is 
important to note that TEDS is an admission-based system, and TEDS 
admissions do not represent individuals, because a given individual 
admitted to treatment twice within a given year would be counted as two 
admissions. TEDS includes facilities that are licensed or certified by 
the State substance abuse agency to provide substance abuse treatment 
and that are required by the States to provide TEDS client-level data. 
Facilities that report TEDS data are those that receive State alcohol 
and/or drug agency funds for the provision of alcohol and/or drug 
treatment services. The primary goal for TEDS is to monitor the 
characteristics of treatment episodes for substance abusers.
    Primary marijuana abuse accounted for 13% of TEDS admissions in 
1998, the latest year for which data are available. In general, most of 
the individuals admitted for marijuana were white young males. 
Marijuana use began at an early age among primary marijuana admissions 
and more than half of the admitted patients had first used marijuana by 
the age of 14 and 92% by the age of 18. More than half of marijuana 
treatment admissions were referred through the criminal justice system.
    Approximately one-third of those who were admitted for primary 
marijuana abuse use the drug daily. Between 1992 and 1998, the 
proportion of admissions for primary marijuana use increased from 6% to 
13%, whereas the proportion of admissions for primary cocaine use 
declined from 18% in 1992 to 15% in 1998. The proportion of opiate 
admissions increased from 12% in 1992 to 15% in 1998 and alcohol 
accounted for about half (47%) of all TEDS admissions in 1998. 
Marijuana has not been associated with other drugs in 30.8% of the 
primary marijuana admissions that corresponds to 4.1% of all 
admissions. Secondary use of alcohol was reported by 38.2% of the 
marijuana admissions and secondary cocaine use was reported by 4% of 
admissions for primary marijuana abuse. The combination marijuana/
alcohol/cocaine accounts for 8.5% of marijuana primary admissions and 
1.1% of all admissions.
    The TEDS Report concludes that, ``Overall, TEDS admissions data 
confirm that those admitted to substance abuse treatment have problems 
beyond their dependence on drugs and alcohol, being disadvantaged in 
education and employment when compared to the general population after 
adjusting for age, gender, and race/ethnicity distribution differences 
between the general population and the TEDS. It is not possible to 
conclude cause and effect from TEDS data--whether substance abuse 
precedes or follows the appearance of other life problems--but the 
association between problems seems clear.''

NIDA's Community Epidemiology Work Group (CEWG, 1999)

    The CEWG is a network composed of epidemiologic and ethnographic 
researchers from major metropolitan areas of the United States and 
selected countries from abroad that meets semiannually to discuss the 
current epidemiology of drug abuse. Large-scale databases used in 
analyses include TEDS; DAWN; the Arrestee Drug Abuse Monitoring (ADAM) 
program funded by the National Institute of Justice; information on 
drug seizures, price, and purity from the Drug Enforcement 
Administration; Uniform Crime Reports maintained by the Federal Bureau 
of Investigation and Poison Control Centers. These data are enhanced 
with qualitative information obtained from ethnographic research, focus 
groups, and other community-based sources. Although data from TEDS and 
DAWN have been previously discussed this document, the analysis offered 
by the CEWG gives a more descriptive overview of individual 
geographical areas. In 1999, marijuana indicators were stable in 17 of 
the 21 CEWG areas. Indicators were mixed in two areas (Atlanta and 
Baltimore) and increased in two (Los Angeles and St. Louis). Despite 
the stability of certain indicators, marijuana abuse remains a serious 
problem in CEWG areas. In Atlanta, marijuana is the second most 
prevalent drug on the market and is increasingly used by a wide variety 
of people mostly white males and young adolescents. In St. Louis, 
marijuana indicators are increasing and DAWN marijuana ED mentions rose 
33.3% from the last half of 1998 to the first half of 1999. Treatment 
admissions rose 40.1% from the second half of 1998 to the first

[[Page 20050]]

half of 1999, and another 9.6% in the second half of 1999.
    In recent years, the proportion of primary marijuana abusers 
entering drug abuse treatment programs has been increasing in many CEWG 
cities. For example, between 1998 and the first semester of 1999, drug 
treatment admissions for primary marijuana abuse increased from 15.2% 
to 20.3% in Atlanta. In the first half of 1999, primary marijuana 
abusers represented 18.8% of drug treatment admissions in New York City 
compared with 16.6% in the first half of 1998. In the first half of 
1999, primary marijuana abuse represented 41.2% of all drug treatment 
admissions in Denver and totaled 3,179. The number of primary marijuana 
admissions in St. Louis increased dramatically in the first half of 
1999, representing 40.8% of treatment admissions.
    The CEWG reports an increase in problems associated with marijuana 
that they attribute to the drug's greater availability/potency, its 
relative low cost, and a public attitude that use of marijuana is less 
risky than use of other drugs.
5. The Scope, Duration, and Significance of Abuse
    According to the National Household Survey on Drug Abuse and the 
Monitoring the Future study, marijuana remains the most extensively 
used illegal drug in the US, with 34.6% of individuals over age 12 
(76.4 million) and 49.7% of 12th graders having tried it at least once 
in their lifetime. While the majority of individuals (85.3%) who have 
tried marijuana do not use the drug monthly, 11.2 million individuals 
(14.7%) report that they used marijuana within the past 30 days. An 
examination of use among various age cohorts demonstrates that monthly 
use occurs primarily among college age individuals, with use dropping 
off sharply after age 25.
    The Drug Abuse Warning Network data show that among 18-25 year 
olds, there was a 19% increase in 1999 for marijuana emergency 
department mentions. The fact that this age cohort had the greatest 
degree of acute adverse reactions to marijuana might be expected given 
that this group has the largest prevalence of marijuana use. Marijuana 
was commonly associated with alcohol and cocaine.
    According to 1999 DAWN data, there were 187 deaths mentions where 
marijuana was the only drug reported, out of the total 664 medical 
examiners episodes involving marijuana in 1999. In the majority of the 
medical examiners episodes marijuana was associated with alcohol, 
cocaine, and morphine.
    Data from the Treatment Episode Data Set confirm that 69% of 
admissions to drug treatment programs for primary marijuana abuse also 
had concurrent use of alcohol and other drugs. The TEDS report also 
emphasizes that individuals who are admitted for drug treatment have 
multiple disadvantages in education and employment compared to the 
general population. Individuals most likely to develop dependence on 
marijuana have a higher rate of associated psychiatric disorders or are 
socializing with a delinquent crowd.
6. What, if Any, Risk There is to the Public Health
    The risk to the public health as measured by quantifiers such as 
emergency room episodes, marijuana-related deaths, and drug treatment 
admissions is discussed in full in sections 1, 4, and 5 above. 
Accordingly, this section focuses on the health risks to the individual 
user. All drugs, both medicinal and illicit, have a broad range of 
effects on the individual user that are dependent on dose and duration 
of usage. It is not uncommon for a FDA approved drug product to produce 
adverse effects even at doses in the therapeutic range. Such adverse 
responses are known as ``side effects''. When determining whether a 
drug product is safe and effective for any indication, FDA performs a 
thorough risk-benefit analysis to determine whether the risks posed by 
the drug product's potential or actual side effects are outweighed by 
the drug product's potential benefits. As marijuana is not approved for 
any use, any potential benefits attributed to marijuana use have not 
been found to be outweighed by the risks. However, cannabinoids have a 
remarkably low acute lethal toxicity despite potent psychoactivity and 
pharmacologic actions on multiple organ systems.
    The consequences of marijuana use and abuse are discussed below in 
terms of the risk from acute and chronic use of the drug to the 
individual user (IOM, 1999) (see also the discussion of the central 
nervous system effects, cognitive effects, cardiovascular and autonomic 
effects, respiratory effects, and the effect on the immune system in 
Section 2):
    Risks from acute use of marijuana:
    Acute use of marijuana causes an impairment of psychomotor 
performance, including performance of complex tasks, which makes it 
inadvisable to operate motor vehicles or heavy equipment after using 
marijuana. People who have or are at risk of developing psychiatric 
disorders may be the most vulnerable to developing dependence on 
marijuana. Dysphoria is a potential response in a minority of 
individuals who use marijuana.
    Risks from chronic use of marijuana:
    Marijuana smoke is considered to be comparable to tobacco smoke in 
respect to increased risk of cancer, lung damage, and poor pregnancy 
outcome. An additional concern includes the potential for dependence on 
marijuana, which has been assessed to be rare among the general 
population but more common among adolescents with conduct disorder and 
individuals with psychiatric disorders. Although a distinctive 
marijuana withdrawal syndrome has been identified, it is mild and 
short-lived.
    The Diagnostic and Statistical Manual (DSM-IV-SR, 2000) of American 
Psychiatric Association states that the consequences of cannabis abuse 
are as follows:

    [P]eriodic cannabis use and intoxication can interfere with 
performance at work or school and may be physically hazardous in 
situations such as driving a car. Legal problems may occur as a 
consequence of arrests for cannabis possession. There may be 
arguments with spouses or parents over the possession of cannabis in 
the home or its use in the presence of children. When psychological 
or physical problems are associated with cannabis in the context of 
compulsive use, a diagnosis of Cannabis Dependence, rather than 
Cannabis Abuse, should be considered.

Individuals with Cannabis Dependence have compulsive use and associated 
problems. Tolerance to most of the effects of cannabis has been 
reported in individuals who use cannabis chronically. There have also 
been some reports of withdrawal symptoms, but their clinical 
significance is uncertain. There is some evidence that a majority of 
chronic users of cannabinoids report histories of tolerance or 
withdrawal and that these individuals evidence more severe drug-related 
problems overall. Individuals with Cannabis Dependence may use very 
potent cannabis throughout the day over a period of months or years, 
and they may spend several hours a day acquiring and using the 
substance. This often interferes with family, school, work, or 
recreational activities. Individuals with Cannabis Dependence may also 
persist in their use despite knowledge of physical problems (e.g., 
chronic cough related to smoking) or psychological problems (e.g., 
excessive sedation and a decrease in goal-oriented activities resulting 
from repeated use of high doses).

[[Page 20051]]

7. Its Psychic or Physiologic Dependence Liability
    Tolerance can develop to marijuana-induced cardiovascular and 
autonomic changes, decreased intraocular pressure, sleep and sleep EEG, 
mood and behavioral changes (Jones et al., 1981). Down-regulation of 
cannabinoid receptors has been suggested as the mechanism underlying 
tolerance to the effects of marijuana (Rodriguez de Fonseca et al., 
1994). Pharmacological tolerance does not indicate the physical 
dependence liability of a drug.
    In order for physical dependence to exist, there must be evidence 
for a withdrawal syndrome. Although pronounced withdrawal symptoms can 
be provoked from the administration of a cannabinoid antagonist in 
animals who had received chronic THC administration, there is no overt 
withdrawal syndrome behaviorally in animals under conditions of natural 
discontinuation following chronic THC administration. The marijuana 
withdrawal syndrome is distinct but mild compared to the withdrawal 
syndromes associated with alcohol and heroin use, consisting of 
symptoms such as restlessness, mild agitation, insomnia, nausea and 
cramping that resolve after 4 days (Budney et al., 1999; Haney et al., 
1999). These symptoms are comparable to the decreased vigor, increased 
fatigue, sleepiness, headache, and reduced ability to work seen with 
caffeine withdrawal (Lane et al., 1998). However, marijuana withdrawal 
syndrome has only been reported in adolescents who were inpatients for 
substance abuse treatment or in individuals who had been given 
marijuana on a daily basis during research conditions. Physical 
dependence on marijuana is a rare phenomenon compared to other 
psychoactive drugs and if it develops, it is milder when marijuana is 
the only drug instead of being used in combination with other drugs.
    TEDS data for 1998 show that 37.9% of admissions for treatment for 
primary marijuana use met DSM IV criteria for cannabis dependence, 
whereas 27.7% met DSM IV criteria for cannabis abuse. Taken in the 
context of the total number of admissions, a DSM IV diagnosis for 
cannabis dependence represented 6.6%, and a diagnosis for cannabis 
abuse represented 4.9%, of all subjects admitted to treatment. In 
contrast, opioid and cocaine dependence was the DSM diagnosis of 12.2% 
and 12.6% of all admissions, respectively. (See Section 6 regarding 
marijuana abuse and dependence).
    According to the NHSDA, data discussed above in Section 1, 6.8 
million Americans used marijuana weekly in 1998. In addition, the DAWN 
data discussed in Section 4 indicates that 34.2% of the 87,150 ED 
marijuana mentions in 1999 were related to episodes in which the motive 
for drug intake was primarily dependence. It should be emphasized that 
the patient-reported ``motive'' for the drug intake applies to the 
entire episode and since more than one drug can be mentioned per 
episode, it may not apply to one specific drug. DAWN data do not 
distinguish the drug responsible for the ED visit from others used 
concomitantly. Finally, the CEWG data discussed in Section 4 above 
reports an increase in the proportion of primary marijuana users 
entering drug abuse treatment programs. Thus, there is evidence among a 
certain proportion of marijuana users for a true psychological 
dependence syndrome.
8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled Under This Article
    Marijuana is not an immediate precursor of another controlled 
substance.

C. Findings and Recommendation

    After considering the scientific and medical evidence presented 
under the eight factors above, FDA finds that marijuana meets the three 
criteria for placing a substance in Schedule I of the CSA under 21 
U.S.C. 812(b)(1). Specifically:
1. Marijuana Has a High Potential for Abuse
    11.2 million Americans used marijuana monthly in 1999 and 1998 data 
indicate that 6.8 million Americans used marijuana weekly. A 1999 study 
indicates that by 12th grade, 37.8% of students report having used 
marijuana in the past year, and 23.1 % report using it monthly. In 
1999, 87,150 emergency department episodes were induced by or related 
to the use of marijuana/hashish, representing 16% of all drug-related 
episodes. The primary motive for drug intake in 34.2 % of those 
episodes was reported to be dependence. DAWN data from that same year 
show that out of 664 medical examiner episodes involving marijuana, 
marijuana was the only drug reported in 187 deaths. In recent years, 
the proportion of primary marijuana abusers entering drug abuse 
treatment programs has been increasing in major U.S. cities, ranging 
from 19% in New York City to 41% in St. Louis and Denver.
    Data show that humans prefer higher doses of marijuana to lower 
doses, demonstrating that marijuana has dose-dependent reinforcing 
effects. Marijuana has relatively low levels of toxicity and physical 
dependence as compared to other illicit drugs. However, as discussed 
above, physical dependence and toxicity are not the only factors to 
consider in determining a substance's abuse potential. The large number 
of individuals using marijuana on a regular basis and the vast amount 
of marijuana that is available for illicit use are indicative of 
widespread use. In addition, there is evidence that marijuana use can 
result in psychological dependence in a certain proportion of the 
population.
2. Marijuana Has No Currently Accepted Medical Use in Treatment in the 
United States
    The FDA has not approved a new drug application for marijuana. The 
opportunity for scientists to conduct clinical research with marijuana 
has increased recently due to the implementation of DHHS policy 
supporting clinical research with botanical marijuana. While there are 
INDs for marijuana active at the FDA, marijuana does not have a 
currently accepted medical use for treatment in the United States nor 
does it have an accepted medical use with severe restrictions.
    A drug has a ``currently accepted medical use'' if all of the 
following five elements have been satisfied:
    a. The drug's chemistry is known and reproducible;
    b. There are adequate safety studies;
    c. There are adequate and well-controlled studies proving efficacy;
    d. The drug is accepted by qualified experts; and
    e. The scientific evidence is widely available.

Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. 
Cir. 1994).
    Although the chemistry of many cannabinoids found in marijuana have 
been characterized, a complete scientific analysis of all the chemical 
components found in marijuana has not been conducted. Safety studies 
for acute or subchronic administration of marijuana have been carried 
out through a limited number of Phase 1 clinical investigations 
approved by the FDA, but there have been no studies that have 
scientifically assessed the efficacy of marijuana for any medical 
condition. A material conflict of opinion among experts precludes a 
finding that marijuana has been accepted by qualified experts. At this 
time, it is clear

[[Page 20052]]

that there is not a consensus of medical opinion concerning medical 
applications of marijuana.
    Alternately, a drug can be considered to have ``a currently 
accepted medical use with severe restrictions'' (21 U.S.C. 
812(b)(2)(B)). Although some evidence exists that some form of 
marijuana may prove to be effective in treating a number of conditions, 
research on the medical use of marijuana has not progressed to the 
point that marijuana can be considered to have a ``currently accepted 
medical use with severe restrictions.''
3. There Is a Lack of Accepted Safety for Use of Marijuana Under 
Medical Supervision
    There are no FDA-approved marijuana products. Marijuana does not 
have a currently accepted medical use in treatment in the United States 
or a currently accepted medical use with severe restrictions. As 
discussed earlier, the known risks of marijuana use are not outweighed 
by any potential benefits. In addition, the agency cannot conclude that 
marijuana has an acceptable level of safety without assurance of a 
consistent and predictable potency and without proof that the substance 
is free of contamination. If marijuana is to be investigated more 
widely for medical use, information and data regarding the chemistry, 
manufacturing and specifications of marijuana must be developed. 
Therefore, FDA concludes that, even under medical supervision, 
marijuana has not been shown to have an acceptable level of safety.
    FDA therefore recommends that marijuana be maintained in Schedule I 
of the CSA.

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Additional Scientific Data Considered by the Drug Enforcement 
Administration in Evaluating Jon Gettman's Petition To Initiate 
Rulemaking Proceedings To Reschedule Marijuana

Drug and Chemical Evaluation Section, Office of Diversion Control, Drug 
Enforcement Administration, March 2001

Introduction

    On July 10, 1995, Jon Gettman petitioned the Drug Enforcement 
Administration (DEA) to initiate rulemaking proceedings to reschedule 
marijuana. Marijuana is currently listed in schedule I of the 
Controlled Substances Act (CSA).
    Mr. Gettman proposed that DEA promulgate a rule stating that 
``there is no scientific evidence that [marijuana has] sufficient abuse 
potential to warrant schedule I or II status under the [CSA].''
    In accordance with the CSA, DEA gathered the necessary data and, on 
December 17, 1997, forwarded that information along with Mr. Gettman's 
petition to the Department of Health and Human Services (HHS) for a 
scientific and medical evaluation and scheduling recommendation. On 
January 17, 2001, HHS forwarded to DEA its scientific and medical 
evaluation and scheduling recommendation. The CSA requires DEA to 
determine whether the HHS scientific and medical evaluation and 
scheduling recommendation and ``all other relevant data'' constitute 
substantial evidence that the drug should be rescheduled as proposed in 
the petition. 21 U.S.C. 811(b). This document contains an explanation 
of the ``other relevant data'' that DEA considered.
    In deciding whether to grant a petition to initiate rulemaking 
proceedings, DEA must consider eight factors specified in 21 U.S.C. 
811(c). The information contained in this document is organized 
according to these eight factors.

(1) Its Actual or Relative Potential for Abuse

    Evaluation of the abuse potential of a drug is obtained, in part, 
from studies in the scientific and medical literature. There are many 
preclinical indicators of a drug's behavioral and psychological effects 
that, when taken together, provide an accurate prediction of the human 
abuse liability. Specifically, these include assessments of the 
discriminative stimulus effects, reinforcing effects, conditioned 
stimulus effect, effects on operant response rates, locomotor activity, 
effects on food intake and other behaviors, and the development of 
tolerance and dependence (cf., Brady et al., 1990; Preston et al., 
1997). Clinical studies of the subjective and reinforcing effects in 
substance abusers, interviews with substance abusers, clinical 
interviews with medical professionals, and epidemiological studies 
provide quantitative data on abuse liability in humans and some 
indication of actual abuse trends (cf., deWit and Griffiths, 1991).
    Evidence of actual abuse and patterns of abuse are obtained from a 
number of substance abuse databases, and reports of diversion and 
trafficking. Specifically, data from Drug Abuse Warning Network (DAWN), 
Poison

[[Page 20054]]

Control Centers, System To Retrieve Investigational Drug Evidence 
(STRIDE), seizures and declarations from U.S. Customs, DEA Drug Theft 
Reports and other diversion and trafficking data bases are indicators 
of the pattern, scope, duration and significance of abuse.
Reinforcing Effects in Animals
    As described by the petitioner, the preponderance of preclinical 
studies using animal models had, to recently, shown that \9\-
THC had minimal activity in behavioral paradigms predictive of 
reinforcing efficacy (i.e., self-administration paradigms; Harris et 
al., 1974; Pickens et al., 1973; Deneau and Kaymakcalan, 1971). In 
general, \9\-THC had been shown to be relatively ineffective 
in maintaining self-administration behavior by either the intravenous 
or oral routes (Kaymakcalan, 1973; Harris et al., 1974; Carney et al., 
1977; Mansbach et al., 1994). Under limited experimental parameters, 
\9\-THC self-administration was demonstrated after animals 
were either first trained to self-administer PCP, after a chronic 
cannabinoid history was established or when maintained at 80% reduced 
body weight (Pickens et al., 1973; Deneau and Kaymakcalan, 1971; 
Takahashi and Singer, 1979). However, Tanda, Munzar and Goldberg of the 
Intramural Preclinical Pharmacology Section of the NIDA (2000) have 
clearly demonstrated that THC can act as a strong reinforcer of drug-
taking behavior in an experimental animal model, the squirrel monkey, 
as it does in humans. The self-administration behavior was comparable 
in intensity to that maintained by cocaine under identical conditions 
and was obtained using a range of doses similar to those self-
administered by humans smoking a single marijuana cigarette.
    Although the neuropharmacological actions of \9\-THC 
suggest a powerful brain substrate underlying its rewarding and 
euphorigenic effects, behavioral studies of \9\-THC's 
rewarding effects had been inconclusive. Several reasons for the 
previous inability by a number of laboratories to demonstrate self-
administration of \9\-THC in animals may be its relatively 
slow-onset, its long-lasting behavioral effects and its insolubility in 
physiological saline or water for injection (Mansbach et al., 1994). 
Similar findings have been found in the animal literature with 
nicotine--an avid reinforcer in humans. The strength of THC, like 
nicotine, as a reinforcer in animals may be more dependent on 
supplementary strengthening by ancillary stimuli than is the case for 
other drugs (cf. Henningfield, 1984).
    In other behavioral and pharmacological tests used to assess 
reinforcing efficacy, \9\-THC produced significant effects. 
Specifically, \9\-THC augments responding for intracranial 
self-stimulation by decreasing the reinforcing threshold for brain 
stimulation reward. It also dose-dependently enhances dopamine efflux 
in forebrain nuclei associated with reward and this enhanced efflux 
occurs locally in the terminal fields within brain reward pathways 
(Gardner and Lowinson, 1991; Gardner, 1992; Chen et al., 1993, 1994). 
In conditioned place preference procedures, \9\-THC (2.0 and 
4.0 mg/kg, i.p.) produced significant dose-dependent increases in 
preference for the drug paired chamber, the magnitude of which was 
similar to that seen with 5.0 mg/kg cocaine and 4.0 mg/kg morphine 
(Leprore et al., 1995). However, \9\-THC also produced a 
conditioned place aversion and conditioned taste aversion (Leprore et 
al., 1995; Parker and Gillies, 1995). The development of taste 
aversions with drug administrations that also produce place preferences 
have been described as somewhat of a ``drug paradox'' by Goudie; 
however, this has been found to occur within the ``therapeutic window'' 
of all known drugs of abuse (cf Goudie, 1987). Goudie has concluded 
that drugs can possess both reinforcing and aversive properties at the 
same doses. This fact may underlie the reciprocal relationship between 
the behavioral effects of THC, CBD, and THC+CBD combinations, discussed 
below.
Drug Discrimination in Animals
    Preclinical drug discrimination studies with \9\-THC are 
predictive of the subjective effects of cannabinoid drugs in humans and 
serve as animal models of marijuana and THC intoxication in humans 
(Balster and Prescott, 1992; Wiley et al., 1993b, 1995). In a variety 
of species it has been found that \9\-THC shares 
discriminative stimulus effects with cannabinoids that bind to CNS 
cannabinoid receptors with high affinity (Compton et al., 1993; Jarbe 
et al., 1989; Gold et al., 1992; Wiley et al., 1993b, 1995b; Jarbe and 
Mathis, 1992) and that are psychoactive in humans (Balster and 
Prescott, 1992). Furthermore, recent studies show that the 
discriminative stimulus effects of \9\-THC are mediated via 
the CB1 receptor subtype (Perio et al., 1996).
    Chronic \9\-THC administration to rats produced tolerance 
to the discriminative stimulus effects of \9\-THC, but not to 
its response rate disruptions. Specifically, tolerance to the stimulus 
effects of \9\-THC increased 40-fold when supplemental doses 
of up to 120 mg/kg/day \9\-THC were administered under 
conditions of suspended training (Wiley et al., 1993a).
    The discriminative stimulus effects of \9\-THC appear to 
be pharmacologically specific as non-cannabinoid drugs typically do not 
elicit cannabimimetic effects in drug discrimination studies (Browne 
and Weissman, 1981; Balster and Prescott, 1992, Gold et al., 1992; 
Barrett et al., 1995; Wiley et al., 1995a). Furthermore, these studies 
show that high doses of \9\-THC produce marked response rate 
disruption, immobility, ataxia, sedation and ptosis in rhesus monkeys 
and rats (Wiley et al., 1993b; Gold et al., 1992; Martin et al., 1995).

Clinical Abuse Potential

    Both marijuana and THC can serve as positive reinforcers in humans. 
Marijuana and \9\-THC produced profiles of behavioral and 
subjective effects that were similar regardless of whether the 
marijuana was smoked or taken orally, as marijuana in brownies, or 
orally as THC-containing capsules, although the time course of effects 
differed substantially. There is a large clinical literature 
documenting the subjective, reinforcing, discriminative stimulus, and 
physiological effects of marijuana and THC and relating these effects 
to the abuse potential of marijuana and THC (e.g., Chait et al., 1988; 
Lukas et al., 1995; Kamien et al., 1994; Chait and Burke, 1994; Chait 
and Pierri, 1992; Foltin et al., 1990; Azorlosa et al., 1992; Kelly et 
al., 1993, 1994; Chait and Zacny, 1992; Cone et al., 1988; Mendelson 
and Mello, 1984).
    These listed studies represent a fraction of the studies performed 
to evaluate the abuse potential of marijuana and THC. In general, these 
studies demonstrate that marijuana and THC dose-dependently increases 
heart rate and ratings of ``high'' and ``drug liking'', and alters 
behavioral performance measures (e.g., Azorlosa et al., 1992; Kelly et 
al., 1993, 1994; Chait and Zacny, 1992; Kamien et al., 1994; Chait and 
Burke, 1994; Chait and Pierri, 1992; Foltin et al., 1990; Cone et al., 
1988; Mendelson and Mello, 1984). Marijuana also serves as a 
discriminative stimulus in humans and produces euphoria and alterations 
in mood. These subjective changes were used by the subjects as the 
basis for the discrimination from placebo (Chait et al., 1988).
    In addition, smoked marijuana administration resulted in multiple 
brief episodes of euphoria that were paralleled by rapid transient 
increases in EEG alpha power (Lukas et al., 1995);

[[Page 20055]]

these EEG changes are thought to be related to CNS processes of 
reinforcement (Mello, 1983).
    To help elucidate the relationship between the rise and fall of 
plasma THC and the self-reported psychotropic effects, Harder & 
Rietbrock (1997) measured both the plasma levels of THC and the 
psychological ``high'' obtained from smoking a marijuana cigarette 
containing 1% THC. As can be seen from these data, a rise in plasma THC 
concentrations results in a corresponding increase in the subjectively 
reported feelings of being ``high''. However, as THC levels drop the 
subjectively reported feelings of ``high'' remain elevated. The 
subjective effects seem to lag behind plasma THC levels. Similarly, 
Harder and Rietbrock compared lower doses of 0.3% THC-containing and 
0.1% THC-containing cigarettes in human subjects.
    As can be clearly seen by these data, even low doses of marijuana, 
containing 1%, 0.3% and even 0.1% THC, typically referred to as ``non-
active'', are capable of producing subjective reports and physiological 
markers of being ``high'.
    THC and its major metabolite, 11-OH-THC, have similar psychoactive 
and pharmacokinetic profiles in man ( Wall et al., 1976; DiMarzo et 
al., 1998; Lemberger et al., 1972). Perez-Reyes et al. (1972) reported 
that THC and 11-OH-THC were equipotent in generating a ``high'' in 
human volunteers. However, the metabolite, 11-OH-THC, crosses the 
blood-brain barrier faster than the parent THC compound (Ho et al., 
1973; Perez-Reyes et al., 1976). Therefore, the changes in THC plasma 
concentrations in humans may not be the best predictive marker for the 
subjective and physiological effects of marijuana in humans. Cocchetto 
et al. (1981) have used hysteresis plots to clearly demonstrate that 
plasma THC concentration is a poor predictor of simultaneous occurring 
physiological (heart rate) and psychological (``high'') pharmacological 
effects. Cocchetto et al. demonstrated that the time course of 
tachycardia and psychological responses lagged behind the plasma THC 
concentration-time profile. As recently summarized by Martin & Hall 
(1997, 1998)

    There is no linear relationship between blood [THC] levels and 
pharmacological effects with respect to time, a situation that 
hampers the prediction of cannabis-induced impairment based on THC 
blood levels (p90).
Physical Dependence in Animals
    There are reports that abrupt withdrawal from 
9-THC can produce a mild spontaneous withdrawal 
syndrome in animals, including increased motor activity and grooming in 
rats, decreased seizure threshold in mice, increased aggressiveness, 
irritability and altered operant performance in rhesus monkeys (cf., 
Pertwee, 1991). The failure to observe profound withdrawal signs 
following abrupt discontinuation of the drug may be due to 
9-THC's long half-life in plasma and slowly waning 
levels of drug that continue to permit receptor adaptation.
    Recently the discovery of a cannabinoid receptor antagonist 
demonstrates that a profound precipitated withdrawal syndrome can be 
produced in 9-THC tolerant animals after twice 
daily injections (Tsou et al., 1995) or continuous infusion (Aceto et 
al., 1995, 1996).
Physical Dependence in Humans
    Signs of withdrawal in humans have been demonstrated after studies 
with marijuana and 9-THC. Although the intensity of 
the withdrawal syndrome is related to the daily dose and frequency of 
administration, in general, the signs of 9-THC 
withdrawal have been relatively mild (cf., Pertwee, 1991). This 
withdrawal syndrome has been compared to that of short-term, low dose 
treatment with opioids, sedatives, or ethanol, and includes changes in 
mood, sleep, heart rate, body temperature, and appetite. Other signs 
such as irritability, restlessness, tremor, mild nausea, hot flashes 
and sweating have also been noted (cf., Jones, 1980, 1983).
    Chait, Fischman, & Schuster (1985) have demonstrated an acute 
withdrawal syndrome or ``hangover'' occurring approximately 9 hours 
after a single marijuana smoking episode. Significant changes occurred 
on two subjective measures and on a time production task. In 1973, 
Cousens & DiMascio reported a similar ``hangover'' effect from acute 
administrations of 9-THC. The hangover phenomenon 
or continued ``high'', in the Cousens & DiMascio study, occurred 9 hrs 
after drug administration and was associated with some residual 
temporal disorganization, as well. These residual or hangover effects 
may mimic the withdrawal syndrome, both qualitatively and 
quantitatively, which is expressed after chronic marijuana exposure. 
This acute hangover may reflect a true acute withdrawal syndrome 
similar to that experienced from high acute alcohol intake. The 
presence of an acute withdrawal syndrome after drug administration has 
been suggested to represent a physiological compensatory rebound by 
which chronic administration of the drug will eventually potentiate and 
produce dependence and the potential for continued abuse (Gauvin, Cheng 
& Holloway, 1993).
    Crowley et al. (1998) screened marijuana users for DSM-IIIR 
dependence criteria. Of the 165 males and 64 female patients that met 
the criteria, 82.1% were found to have co-morbid conduct disorders; 
17.5% had major depression; and 14.8% had a diagnosis of attention-
deficit/hyperactivity disorder. These results also showed that most 
patients claimed to have ``serious problems'' from cannabis use. The 
data also indicated that for adolescents with conduct problems, 
cannabis use was not benign, and that the drug served as a potent 
reinforcer for further cannabis usage, producing dependence and 
withdrawal.
    Kelly & Jones (1992) quantified concentrations of THC and its 
metabolites in both plasma and urine after a 5 mg intravenous dose of 
THC was administered to frequent and infrequent marijuana smokers. The 
frequent smokers were users who smoked marijuana almost daily for at 
least two years. The infrequent smokers were users who smoked marijuana 
no more than two to three times per month but had done so for at least 
two years. Pharmacokinetic parameters after intravenously administered 
THC revealed no significant differences between frequent and infrequent 
marijuana users on area under the time-effect curve (AUC), volume of 
distribution, elimination half-lives of parent THC and metabolites in 
plasma and urine. There were also no group differences in metabolic or 
renal clearances. The authors concluded that there was no evidence for 
metabolic or dispositional tolerance between the two groups of 
subjects. Kelly and Jones also reported that tolerance was not evident 
in heart rate, diastolic blood pressure, skin temperature, and the 
degree of psychological ``high'' from the i.v. administration of THC.
    In two separate reports, Haney et al. have recently described 
abstinence symptoms of an acute withdrawal syndrome following high (30 
mg q.i.d.) and low (20 mg q.i.d) dose administrations of oral THC 
(Haney et al., 1999a) and following 5 puffs of high (3.1%) and low 
(1.8%) THC-containing smoked marijuana cigarettes (Haney et al., 
1999b). Abstinence from oral THC increased ratings of ``anxious'', 
``depressed'', and ``irritable'', and decreased the reported quantity 
and quality of sleep and decreased food intake by 20-30% compared to 
baseline. Abstinence from as low as 5 controlled puffs of active 
marijuana smoking increased ratings of ``anxious'', ``irritable'' and 
``stomach pain'', and

[[Page 20056]]

significantly decreased food intake. The 5 controlled puffs of 5 second 
duration each were drawn from 2 separate marijuana cigarettes (3 puffs 
from one, 2 puffs from the other. The smoke was held for 40 seconds and 
then exhaled. All subjects reported significant increases on subjective 
measures of ``high'', ``good drug effect'', and ``stimulated'', as well 
as ``mellow'', ``content'', and ``friendly'' as a result of this 
limited and controlled draw of THC. Both of these studies have 
delineated a withdrawal syndrome from concentrations of THC 
significantly lower than those reported in any other previous study 
and, for the first time, clearly identified a marijuana withdrawal 
syndrome detected at low levels of THC exposure that do not produce 
tolerance. The abstinence syndrome was not limited to subjective state 
changes but was also quantified using a cognitive/memory test battery.
    In a related study, Khouri et al (1999) found that long-term heavy 
marijuana users became more aggressive during abstinence from marijuana 
than did former or infrequent users. Previous dependence studies have 
relied largely on patients' subjective reports of a range of symptoms. 
Khouri et al. examined a single symptom--aggression. The authors 
concluded that marijuana abstinence is associated with unpleasant 
behavioral symptoms that may contribute to continued marijuana use.
    Kouri & Pope (2000) examined three groups of marijuana users during 
a 28-day supervised abstinence period. Current marijuana users 
experienced significant increases in anxiety, irritability, physical 
tension, and physical symptoms and decreases in mood and appetite 
during marijuana withdrawal. These symptoms were most pronounced during 
the initial 10 days of abstinence, bust some were present for the 
entire 28-day withdrawal period. The findings from this study reveal 
that chronic heavy users of marijuana experience a number of withdrawal 
symptoms during abstinence and clearly demonstrate a ``marijuana 
dependence syndrome'' in humans.
    These data suggest that dependence on THC may in fact be an 
important consequence of repeated, daily exposure to cannabinoids and 
that daily marijuana use may be maintained, at least in part, by the 
alleviation of abstinence symptoms. Relevant to the present petition, 
the Haney et al. study is the first report demonstrating this syndrome 
with extremely low concentrations of THC.
Results of THC Dose Comparison Studies
    There are reports in the scientific literature that evaluated dose-
related subjective and reinforcing effects of Cannabis sativa in 
humans. These studies have assessed the subjective and reinforcing 
effects of cannabis cigarettes containing different potencies of THC 
and/or which have manipulated the THC dose by varying the volume of THC 
smoke inhaled (Azorlosa et al., 1992; Lukas et al., 1995; Chait et al., 
1988; Chait and Burke, 1994; Kelly et al., 1993).
    Chait et al. (1988) studied the discriminative stimulus effects of 
smoked marijuana cigarettes containing THC contents of 0%, 0.9%, 1.4%, 
2.7%. Marijuana smokers were trained to discriminate smoked marijuana 
from placebo using 4 puffs of a 2.7%-THC cigarettes. Subjective ratings 
of ``high'', and physiological measures (i.e., heart rate) were 
significantly and dose-dependently increased after smoking the 0.9%, 
1.4%, 2.7%.
    Marijuana cigarettes containing 1.4% THC completely substituted for 
2.7%-THC on drug identification tasks, however, 0.9%-THC did not. The 
authors found that the onset of discriminative stimulus effects was 
within 90 seconds after smoking began (after the first two puffs). 
Since the 1.4%-THC cigarette substituted for 2-puffs of the 2.7%-THC 
cigarette, the authors estimate that an inhaled dose of THC as low as 3 
mg can produce discriminable subjective effects.
    Similarly, Lukas et al. (1995) reported that marijuana cigarettes 
containing either 1.26% or 2.53% THC produced significant and dose-
dependent increases in level of intoxication and euphoria in male 
occasional marijuana smokers. Four of the six subjects that smoked the 
1.26%-THC cigarette reported marijuana effects and 75% of these 
subjects reported euphoria. All six of the subjects that smoked 2.53% 
THC reported marijuana effects and euphoria. Peak levels of self-
reported intoxication occurred at 15 and 30 minutes after smoking and 
returned to control levels by 90-105 minutes. There was no difference 
between latency to or duration of euphoria after smoking either the 
1.26% or 2.53% THC cigarettes. The higher dose-marijuana cigarette 
produced a more rapid onset and longer duration of action than the 
lower dose marijuana cigarette (1.26% THC). Plasma THC levels peaked 5-
10 minutes after smoking began; the average peak level attained after 
the low- and high-dose marijuana cigarette was 36 and 69 ng/ml 
respectively.
    In order to determine marijuana dose-effects on subjective and 
performance measures over a wide dose range, Azorlosa et al. (1992) 
evaluated the effects of 4, 10, or 25 puffs from marijuana cigarettes 
containing 1.75 or 3.55% THC in seven male moderate users of marijuana. 
Orderly dose-response curves were produced for subjective drug effects, 
heart rate, and plasma concentration, as a function of THC content and 
number of puffs. After smoking the 1.75% THC cigarette, maximal plasma 
THC levels were 57 ng/ml immediately after smoking, 18.3 ng/ml 15 
minutes after smoking, 10.3 ng/ml 30 minutes after smoking, and 7.7 ng/
ml 45 minutes after smoking.
    The study also showed that subjects could smoke more of the low THC 
cigarette to produce effects that were similar to the high THC dose 
cigarette (Azorlosa et al., 1992). There were nearly identical THC 
levels produced by 10-puff low-THC cigarette (98.6 ng/ml) and 4-puff 
high THC cigarette (89.4 ng/ml). Similarly, the subjective effects 
ratings, including high, stoned, impaired, confused, clear-headed and 
sluggish, produced under the 10 puff low- and high-THC and 25 puff low-
THC conditions did not differ significantly from each other.
    As with most drugs of abuse, higher doses of marijuana are 
preferred over lower dose. Although not preferred, these lower doses 
still produce cannabimimetic effects. Twelve regular marijuana smokers 
participated in a study designed to determine the preference of a low 
potency (0.64%-THC) vs. a high potency (1.95%-THC) marijuana cigarette 
(Chait and Burke, 1994). The subjects first sampled the marijuana of 
two different potencies in one session, then chose which potency and 
how much to smoke. During sampling sessions, there were significant 
dose-dependent increases in heart rate and subjective effects, 
including ratings of peak ``high'', strength of drug effects, 
stimulated, and drug liking. During choice sessions, the higher dose 
marijuana was chosen over the lower dose marijuana on 87.5% of 
occasions. Not surprising, there was a significant positive correlation 
between the total number of cigarettes smoked and the ratings of 
subjective effects, strength of drug effect, drug ``liking'', expired 
air carbon monoxide, and heart rate increases. The authors state it is 
not necessary valid to assume that the preference observed in the 
present study for the high-potency marijuana was due to greater CNS 
effects from its higher THC content. The present study found that the 
low- and high-potency marijuana cigarettes also differ on

[[Page 20057]]

several sensory dimensions; the high-potency THC was found to be 
reported as ``fresher'' and ``hotter''. Other studies found that 
marijuana cigarettes containing different THC contents varied in 
sensory dimensions (cf., Chait et al., 1988; Nemeth-Coslett et al., 
1986).
    As summarized by Martin & Hall for the United Nations only a small 
amount of cannabis (e.g. 2-3 mg of available THC) is required to 
produce a brief pleasurable high for the occasional user and a single 
joint may be sufficient for two or three individuals. Using these data 
and those of Harder & Reitbroch (1997, above), a one gram cigarette 
containing 1% THC containing cannabis, would contain 10 mg of THC--a 
dose well capable of producing a social high.
    Carlini et al. (1974) examined 33 subjects who smoked marijuana 
cigarettes with different ratios of constituent cannabinoids. The plant 
containing 0.82% THC produced larger than expected results based on the 
estimates from the THC content.
    Smoking a 250 mg cigarette containing 5.0 mg of 
9-THC induced more reactions graded 3 and 4 than 10 
or 20 mg of 9-THC. It was further observed that the 
psychological effects (subjective ``high'') started around 10 min after 
the end of the inhalation, and reached a maximum 20 to 30 min later, 
subsiding within 1 to 3 hrs. The peak of psychological disturbances, 
therefore, did not coincide in time with the peak of pulse rate 
effects. Carlini et al., suggested that other constituents of the 
marijuana were interacting synergistically with the THC to potentiate 
the subjective response induced by the smoking of the cigarette. 
Karniol and colleagues (1973, 1974) have clearly demonstrated that 
cannabidiol (CBD) blocks some of the effects induced by THC, such as 
increased pulse rates and disturbed time perception. More importantly, 
CBD blocked some of the psychological effects of THC, but not by 
altering the quantitative or intensity of the psychological reactions. 
CBD seemed better able to block the aversive effects of THC. CBD 
changed the symptoms reported by the subjects in such a way that the 
anxiety component produced by THC administration was actually reduced. 
The animal subjects of one study showed greater analgesia scores with a 
CBD+THC combination (1973) and the human subjects from the other study 
(1974) showed less anxiety and panic but reported more pleasurable 
effects. CBD may be best seen as an ``entourage'' compound (Mechoulam, 
Fride, DiMarzo, 1998) which is administered along with THC and results 
in a functional potentiation of THC's behavioral and subjective 
effects. This potentiation can be in both the intensity and/or duration 
of the high induced by marijuana. According to Paris & Nahas (1984) the 
CBD:THC ratio in industrial or fiber type hemp is 2:1. Relevant to the 
current petition, the CBD:THC ratio producing the greatest increase in 
euphoria in the Karniol, et al. studies was 2:1 (60:30 mg).
    Jones & Pertwee (1972) were first to report that the presence of 
cannabidiol inhibited the metabolism of THC and its active metabolite. 
These data were soon replicated by Nilsson et al., (1973). Bronheim et 
al., (1995) examined the effects of CBD on the pharmacokinetic profile 
of THC content in both blood and brains of mice. CBD pretreatments 
produced a modest elevation in THC-blood levels; area under the 
kinetics curve of THC was increased by 50% as a function of decreased 
clearance. CBD pretreatments also modestly increased the 
Cmax, AUC, and half-life of the major THC metabolites in the 
blood. The THC kinetics function showed a 7- to 15-fold increase in the 
area under the curve, a 2- to 4-fold increase in the half-life, as well 
as the tmax. CBD pretreatments resulted in large increases 
in area under the curves and half-lives of all the THC metabolites in 
the mice brains. The inhibition of the metabolism of THC and its 
psychoactive metabolites by CBD may underlie the potentiation in the 
subjective effects of THC by CBD in humans.
    In addition to THC, hemp material contains a variety of other 
substances (e.g., Hollister, 1974), including other cannabinoids such 
as cannabidiol (CBD) and cannabinol (CBN). One comprehensive review 
described the activities of 300 cannabinoid compound in preclinical 
models (Razdan, 1986). Since CBD is always present in preparations of 
cannabis, it may represent a high CBD:THC ratio in the case of low THC 
cannabis. Therefore, it is important to understand the interactions of 
cannabidiol and 9-THC.
    Structure-activity studies of cannabinoid compounds characterized 
cannabidiol in relationship to 9-THC and other 
cannabinoids (Martin et al., 1981; Little et al., 1988). These and 
other studies have found that cannabidiol was inactive and did not 
produce neuropharmacological effects or discriminative stimulus, 
subjective effects and behavioral effects predictive of psychoactive 
subjective effects (Howlett, 1987; Howlett et al., 1992; c.f., Hiltunen 
and Jarbe, 1986; Perez-Reyes et al., 1973; Zuardi et al., 1982; Karniol 
et al., 1974).
    Other studies have reported that cannabidiol has cannabinoid 
properties, including anticonvulsant effects in animal and human models 
(Consroe et al., 1981; Carlini & Cunha, 1981; Doyle and Spence, 1995), 
hypnotic effects (Monti, 1977), anxiolytic effects (Musty, 1984; 
Onaivi, Geen, & Martin, 1990; Guimarares et al., 1990; 1994) and rate-
decreasing effects on operant behavior (Hiltunen et al., 1988).
    Experiments with cannabidiol in combination with THC have found 
that certain behavioral responses induced by THC (i.e., operant, 
schedule-controlled responding) were attenuated by cannabidiol (Borgen 
and Davis, 1974; Brady and Balster, 1980; Consroe et al., 1977; Dalton 
et al., 1976; Kraniol and Carlini, 1973; Karniol et al., 1974; Welburn 
et al., 1976; Zuardi and Karniol, 1983; Zuardi et al., 1981, 1982; 
Hiltunen et al., 1988). However, other affects produced by THC are 
augmented or prolonged by the combined administration of CBD and THC or 
marijuana extract (Chesher and Jackson, 1974; Hine et al., 1975a,b; 
Fernandes et al., 1974; Karniol and Carlini, 1973; Musty and Sands, 
1978; Zuardi and Karniol, 1983; Zuardi et al., 1984). Still other 
studies did not report any behavioral interaction between the CBD and 
THC (Bird et al., 1980; Browne and Weissman, 1981; Hollister and 
Gillespie, 1975; Jarbe and Henricksson, 1974; Jarbe et al., 1977; 
Mechoulam et al., 1970; Sanders et al., 1979; Ten Ham and DeLong, 
1975).
    A study to characterize the interaction between CBD and THC was 
conducted using preclinical drug discrimination procedures. Rats and 
pigeons trained to discriminate the presence or absence of THC, and 
tested with CBD administered alone and in combinations with THC 
(Hiltunen and Jarbe, 1986).
    Specifically, in rats trained to discriminate 3.0 mg/kg, i.p. THC, 
CBD (30.0 mg/kg) was administered alone and in combination with THC 
(0.3 and 1.0 mg/kg, i.p.). In pigeons trained to discriminate 0.56 mg/
kg, i.m. THC, CBD (17.5 mg/kg) was administered alone and in 
combination with THC (0.1, 0.3, and 0.56 mg/kg, i.m.). CBD prolonged 
the discriminative stimulus effects of THC in rats, but did not change 
the time-effect curve for THC in pigeons. In pigeons, the 
administration of CBD did not produce any differential effect under a 
fixed ratio schedule of reinforcement (Hiltunen and Jarbe, 1986).
    These data suggest that CBD may somehow augment or prolong the 
actions of THC in rats and had no effect in pigeons. In the present 
study, the CBD/THC ratios ranged from 30:1 to 100:1 in rats and 
enhanced the stimulus

[[Page 20058]]

effects of THC. However, similar CBD/THC ratios in pigeons (31:1, 58:1 
and 175:1) did not result in any changes to THC's discriminative 
stimulus or response rate effects (Hiltunen and Jarbe, 1986).
    It should be noted that cannabidiol can be easily converted to 
delta-9- and delta-8-tetrahydrocannabinol. Even industrial hemp plant 
material (leaves), containing high concentrations of CBD, can be 
treated in clandestine laboratories to convert the CBD to delta-9-
tetrahydrocannabinol (Mechoulam, 1973) converting a supposedly 
innocuous weed into a potent smoke product.
    In conclusion, the ``entourage'' compound, cannabidiol, does 
contribute to all of the effects ascribed to THC, however it also 
appears to lack cannabimimetic properties. However, there is no 
credible scientific evidence that CBD is a pharmacological antagonist 
at the cannabinoid receptor (Howlett, Evans, & Houston, 1992). There is 
clear evidence that CBD can functionally antagonize some of the 
aversive effects of THC (Dewey, 1986). The data from the scientific 
literature cited above, clearly demonstrate the ability of CBD to 
modify some very specific effects of THC. Most importantly, relative to 
the euphorigenic effects of THC (which contributes to its abuse 
liability), CBD appears to potentiate the psychological or subjective 
effects of THC by potentiating the blood and brain THC and 11-OH-THC 
levels and by functionally blocking the aversive (anxiety-like) 
properties of THC.

Abuse Liability Summary

    Preclinical and clinical experimental data demonstrate that 
marijuana and ``9-THC have similar abuse 
liabilities (i.e., drug discrimination, self-administration, subjective 
effects). Both preclinical and clinical studies show that 
discontinuation of either marijuana or ``9-THC 
administration produces a mild withdrawal syndrome. The effects of THC 
are dose-dependent and several studies have found that low-potency THC 
is behaviorally active and can produce cannabimimetic-like subjective 
and physiological effects.

Actual Abuse

    There are dozens of data collection and reporting systems that are 
useful for monitoring the United States' problem with abuse of licit 
and illicit substances. These data collection and reporting systems 
provide quantitative data on many factors related to abuse of a 
particular substance, including incidence, pattern, consequence and 
profile of the abuser of specific substances (cf., Larsen et al., 
1995).
    Evidence of actual abuse is defined by episodes/mentions in the 
databases indicative of abuse/dependence. Some of the databases that 
are utilized by DEA to provide data relevant to actual abuse of a 
substance include the Drug Abuse Warning Network (DAWN), National 
Household Survey on Drug Abuse, Monitoring the Future survey, FDA's 
Spontaneous Adverse Events Reports, the American Association of Poison 
Control Centers database and reports of the Community Epidemiology Work 
Group (CEWG).
    Drug trafficking and diversion data provide strong evidence that a 
drug or other substance is being abused. In order to determine the 
pattern, incidence, and consequences of abuse and the demographics of 
abusers of a particular substance to be controlled, DEA relies on data 
collected from a number of sources, including the United States 
government as well as state and local law enforcement groups. 
Information from these sources often provides a first indication of an 
emerging pattern of abuse of a particular drug or substance, and when 
taken together with other data sources provide strong evidence that can 
be used in determining a substance's placement in the schedules listed 
in the CSA.
    The evidence from epidemiological studies conclude that marijuana 
use alone and in combination with other illicit drugs is increasing. 
The most recent ``Monitoring the Future Study'', documented increases 
in lifetime, annual and current (within the past 30 days) and daily use 
of marijuana by eighth and tenth graders; this increasing trend began 
in the early 1990's.
    Similarly, according the NIDA's ``National Household Survey'', 
marijuana use is increasing with the greatest increase among the 
younger age groups (12-17 years of age). The frequency of marijuana use 
in the past year increases significantly among 12-17 year olds. This 
survey also found that youths who used marijuana at least once in their 
lives were more likely to engage in violent or other antisocial 
behaviors.
    Marijuana is the most readily available illicit drug in the United 
States. Cannabis is cultivated in remote locations and frequently on 
public lands. Major domestic outdoor cannabis cultivation areas are 
found in California, Hawaii, Kentucky, New York and Tennessee. 
Significant quantities of marijuana were seized from indoor cultivation 
operations; there were 3,532 seizures in 1996 compared to 3,348 seized 
in 1995. Mexico is the major source of foreign marijuana, along with 
lesser amounts from Colombia and Jamaica (NNICC, 1996).
    Domestically, marijuana is distributed by groups or individuals, 
ranging from large sophisticated organizations with controlled 
cultivation and interstate trafficking, to small independent 
traffickers at the local level.
(2) Scientific Evidence of Its Pharmacological Effects, If Known
    Cannabis sativa is unique in that it is the only botanical source 
of the terpenophenolic substances referred to as cannabinoids which are 
responsible for the psychoactive effects of Cannabis. There are roughly 
60 different cannabinoids found in Cannabis (Nahas, 1984; Murphy & 
Bartke, 1992; Agurell, Dewey & Willette, 1984) but the psychoactive 
properties of Cannabis are attributed to one or two of the major 
cannabinoid substances, namely delta-9-tetrahydrocannabinol and delta-
8-tetrahydrocannabinol. In fresh, carefully dried marijuana, up to 95% 
of their cannabinoids are present as (-)-delta-9-(trans)-
tetrahydrocannabinol carboxylic acid (Nahas, 1984; Murphy & Bartke, 
1992; Agurell, Dewey & Willette, 1984). The acid form is not 
psychoactive, but is readily decarboxylated upon heating to yield 
delta-9-tetrahydrocannabinol (neutral form). Therefore, plant material 
could be very high in its ``pro-drug'' acid form and very low in 
neutral form but still be very potent when smoked.
    There are two primary factors that influence THC content: genetic 
predisposition and environmental influences. Genetic factors are 
considered predominant in determining cannabinoid content, although, 
fluctuations in weather conditions have greatly enhanced or diminished 
the THC content.
    Paris & Nahas (1984) have admonished that marijuana is not a single 
uniform plant like many of those encountered in nature, but a rather 
deceptive weed with several hundred variants. The intoxicating 
substances prepared from Cannabis vary considerably in potency 
according to the varying mixtures of different parts of the plant, and 
according to the techniques of fabrication. According to Paris & Nahas, 
this basic botanical fact has been overlooked by physicians and 
educators, who have written about marijuana as a simple, single 
substance, which uniformly yields a low concentration of a single 
intoxicant. In addition to changes due to its own genetic plasticity, 
marijuana has been modified throughout the ages by environmental 
factors and human manipulations, and is not yet a

[[Page 20059]]

stabilized botanical species (Paris & Nahas, 1984).
    According to Paris & Nahas (1984) the terminology used by Fetterman 
et al. (1970, 1971) is somewhat misleading, especially with respect to 
their contention that environmental factors, including climate, are not 
as important as heredity in determining the cannabinoid content of 
cutigens. The analyses of Fetterman et al., (1970) were performed 
according to the technique by Doorenbos et al., (1971) on plant 
materials from variants that had been cut at the stem beneath the 
lowest leaves and air-dried. Seeds, bracts, flowers, leaves and small 
stems were then stripped from the plant. Most of the small stems were 
removed by a 10-mesh screen, and the seeds were eliminated with a 
mechanical seed separator. This preparation of marijuana contains less 
seed and stem than most of the illicit material available in the United 
States. Cannabinoids were then extracted from the plant material and 
analyzed by standard techniques.
    Other systems of separating Cannabis into drug, intermediate and 
non-drug type have been developed. These are typically determined by 
chemical analyses based upon the method described by Doorenbos (1971) 
which utilizes manicured portions of the Cannabis plant only in 
determining percent concentration.
    Cannabis sativa has been referred to as a widely distributed and 
unstabilized species. Cannabis exhibits extreme polymorphism (ability 
to alter, change) in different varieties, dependent upon many factors. 
For example, there are at least twenty strains which are cultivated for 
fiber. There have been many attempts to classify Cannabis as a function 
of intoxicant properties or fiber properties. Such classification 
efforts are dependent upon the age of the sample. And there is no 
totally reliable classification system based on a single chemical 
analysis. The plasticity of the genus has prevented the development of 
such a system (Turner et al. 1980a,b).
    In a study where twelve strains of Cannabis were grown out of doors 
in Southern England (Fairbairn and Liebmann, 1974, Fairbairn et al., 
1971), the following were determined:
    1. Warm climate are not necessary for high THC content.
    2. There is considerable THC content variation within and between 
plants.
    3. Quantitative results of tetrahydrocannabinol concentration (THC) 
are highly dependent upon the specific plant part sampled, the stage of 
growth and the size of sample.
    4. Certain strains of Cannabis can be THC or cannabidiol (CBD) rich 
which does not seem to be dependent upon environmental conditions.
    5. However, growing the same strain of Cannabis under different 
lighting conditions can produce plants that range from 2.4 to 4.42% THC 
concentration (based upon an analysis of the upper leaves). And 
finally,
    6. THC concentration are dramatically higher on dried flowering or 
vegetative tops of the plants relative to middle or lower portions.
    In a similar study on the characterization of Cannabis accessions 
with regard to cannabinoid content, vis-a-vis other plant characters 
(deMeijer, 1992), it was determined that:
    1. There exists considerable variation within and among accessions 
for cannabinoid content;
    2. Mean cannabinoid content is strongly affected by year of 
cultivation;
    3. There is no strict relationship between chemical and non-
chemical traits; and,
    4. It is uncommon, but some accessions combine high bark fiber 
content and considerable psychoactive potency.
    In 1993 de Meijer reported the results of a government 
(Netherlands) funded industrial hemp project designed to investigate 
the stem quality, yield, and a comparative analysis to wood fibers. 
deMeijer found that the commercial grade industrial hemp seeds, 
germplasms derived from 0.3% THC chemovars, demonstrated a significant 
variation in the average THC content which ranged from 0.06 to 1.77% in 
the female dry leaf matter. deMeijer concluded by stating,

    Although high bark fiber content does not necessarily exclude 
high THC content, most fiber cultivars have very low THC content and 
thus possess no psychoactive potency

While the data from his own study refutes these conclusions he does 
conclude that the industrial hemp plant does not preclude high THC 
content.
    A review of these and other studies in the scientific literature, 
indicate that THC concentrations vary within portions of the Cannabis 
plant (Hanus et al., 1989, 1975). In some studies, the concentration of 
THC can increase as much as 100% from leafy to flowering portions of 
the same plant. THC concentrations are known to be elevated on the 
upper portions of the plant. In a study published by Fairbairn and 
Liebmann, (1974) there was considerable variations between the 
flowering tops (bracts, flowers, immature fruits at the ends of shoots) 
and leafy portions of some specimens. THC content decreases with age 
and length of leaves (Paris & Nahas, 1984, p 25). The lower, more 
developed leaves have a low cannabinoid content and the top leaves have 
a high cannabinoid content, especially when they are associated with 
the bracts of the plant. Cannabinoids are localized in the upper third 
of the ``stalk'' and in the flowers. Therefore, the THC content of 
specific portions of a plant, which on a whole plant basis did not 
exceed 1%, could significantly exceed this threshold. Very few 
marijuana users actually ``smoke'' the leaves. It is the colas or the 
flowering portions of the plants which are utilized and these are 
exactly the portions of the plant which would be expected to have the 
highest concentration of THC.
    It is clearly recognized that Cannabis presents a high degree of 
genetic plasticity which results in extreme polymorphism in its 
different varieties. The hemp first grown in the United States for 
fiber was of European origin. The type basic to modern American fiber 
production, known as Kentucky, came originally from China. In Europe, 
there are five to six varieties with one considered ``exceptional''--
the Kymington. The plasticity of the European fiber variety has been 
clearly shown (Bouquet, 1951; Hamilton, 1912, 1915). European cultigens 
planted in dry, warm areas of Egypt to supply fiber for rope-making 
were found to produce, within several generations, plants with high 
psycho-active ingredients and very little fiber. Cannabis sativa's 
botanical and chemical characteristics change markedly as a result of 
environmental factors and human manipulation. Doorenbos et al., (1971) 
cultivated a Mexican and Turkish variant in Mississippi for three 
consecutive generations. During that period, the 9-
THC content did not change in the Mexican variant but increased in the 
Turkish variant. In the more controlled environment of a phytotron 
(light, humidity, and nutrition controlled), Braut-Boucher (1978), 
Braut-Boucher & Petiard (1981), Braut-Boucher, Paris, & Cosson (1977) 
and Paris et al., (1975) found that the cannabinoid concentrations rose 
over a similar three year period. The concentrations rose more sharply 
in cool environments (22-12 deg.C: day-night) than in warm environments 
(32-12 deg.C). Some authors have hypothesized that immediate 
environmentally caused changes are individual plant reactions, whereas 
the progressive changes over generations are linked with whole 
populations and constitute a true natural selection. Whether this 
evolution is caused by a change of genetic equilibrium (caused by the 
environment), or by a

[[Page 20060]]

modification of the genetic capacity (over time), is impossible to say 
(Paris & Nahas, 1984).
    In 1974 through 1976 the University of Mississippi cultivated 7 
variants of 12 Cannabis plants discovered and collected in 1973 from 
different areas of Mexico. Cannabinoid content was analyzed weekly 
during the cultivation period. Turner, Elsohly, Lewis, Lopez-Santibanez 
& Carranza (1982) summarized their findings as follows:

    In 1974, vegetative plants of ME-H, ME-K, ME-L, ME-N and ME-O, 
at 13 weeks of age had higher 9-THC content that 
at weeks 12 and 14. They showed minimum 9-THC 
content at week 15. For the most part, 1974 staminate and pistillate 
plants grown in Mississippi produced a low 9-THC 
concentration * * *.

    In all variants, the average 9-THC was higher 
in 1976 than in 1974. Also, a greater fluctuation of 
9-THC was observed in 1976 than in 1974.
    These results further establish that Cannabis Sativa L. is not a 
stable hybrid plant, but rather, represents characteristics more 
similar to an unstable weed.
    Marijuana chemistry is complex and cannot be simplified or 
extrapolated from any one or two ``active compounds''. As early as 1974 
this fact was recognized by the United Nations Division on Narcotic 
Drugs (UN Doc, 1974). As highlighted by Turner (1980), the chemistry of 
THC is not the chemistry of marijuana and the pharmacology of marijuana 
is not the pharmacology of THC. Recent findings do suggest that the 
interactions between cannabinoids is one of many critical factors in 
the analysis of the psychopharmacology of marijuana.
    According to Jones (1980), because of exposure to a wide range of 
plant material and the cultural labeling (almost like advertising) of 
much of the marijuana experience, marijuana users are particularly 
subject to the effects of nonpharmacological variables that alter the 
subjective response to marijuana intoxication (Jones 1971, 1980; 
Cappell & Pliner, 1974; Becker 1967). As reviewed by Jones (1971), a 
number of studies suggest that experienced marijuana users are more 
subject to ``placebo reactions'; that is, a degree of intoxication 
disproportionate to the THC content of the material. This seems 
particularly true if the individuals are exposed to low potency 
marijuana (1.0% THC). Jones believes that this is a result of 
experience and practice at recognizing minimal physiologic cues 
together with the smell, taste and other sensations associated with 
smoking a marijuana cigarette (Jones 1980, 1971). Becker 1967 and 
Cappell & Pliner (1974) have described a number of psychological 
factors (expectancy, social setting, etc.) that appear to 
synergistically interact to help generate the subjective experiences 
engendered by marijuana smoking.
    Domino, Rennick, & Pearl (1976) administered THC injected into 
tobacco cigarettes to male volunteers. Similar to findings described by 
Isbell et al., (1967) they report that 50 g of THC into the 
cigarettes produced a ``social high'', while 250 g/kg was 
``hallucinogenic''. Taking 80 kg as the mean weight of their subjects 
the authors concluded that a 4.0 mg total THC dose produced a ``social 
high''; a hallucinogenic dose was 20 mg total THC by inhalation. A 
standard 1g cigarette of 1% THC fibre-type hemp provides 10 mg of THC. 
Even allowing for a 50% loss of THC from sidestream smoke and 
pyrolysis, smoking this cigarette provides more than enough THC to 
produce a ``social high''.
    In 1968 Weil, Norman, & Nelsen described a set of studies examining 
the physiological and psychological aspects of smoked marijuana. The 
first batch of Mexican grown marijuana used in the study was found to 
contain only 0.3% THC by weight. The potency of this product was 
considered to be ``low'' by the experimenters on the basis of the doses 
needed to produce symptoms of intoxication in the chronic users. This 
low potency marijuana was able to produce a ``high'', but only with two 
1 gram cigarettes. A second batch was used in later studies. Weil, 
Norman, & Nelsen report that marijuana assayed at 0.9% THC (a quantity 
slightly less than the 1% THC limit set forth by the petitioners) was 
rated by the chronic users in the study to be ``good, average'' 
marijuana, neither exceptionally strong nor exceptionally weak compared 
to the usual supplies. Users consistently reported symptoms of 
intoxication after smoking about 0.5 grams of the 0.9% THC containing 
marijuana (half a joint). With the high dose of marijuana (2.0 grams of 
0.9% THC containing marijuana) all chronic users became ``high'' by 
their own accounts and in the judgment of experimenters who had 
observed many persons under the influence of marijuana.
    Agurell & Leander (1971) examined the physiological and 
psychological effects of low THC-containing cannabis in experienced 
users. They reported that 14-29% of the cannabinoid content of the 
cigarette was transferred to the main stream smoke. Based on 
qualitative and quantitative analyses, Agurell & Leander demonstrated 
that as little as 3-5 mg of THC was needed to be absorbed by the lung 
in order to produce a ``normal biological high''. Further, they found 
that as little as 1 mg of absorbed THC was discriminable by all of 
their chronic user subjects.
    In 1982, Barnett, Chiang, Perez-Reyes, & Owens had six subjects 
smoke a 1% THC-containing (industrial hemp, as defined by the 
petitioner) marijuana cigarette. Significant heart rate and subjective 
measures of ``high'' were measured for 2 hours after each cigarette.
    In 1971 Jones reported on the wide variability in THC 
concentrations found in street samples:

    Specimens gathered in the midwestern United States contained 
only 0.1--0.5% THC. Thirty specimens selected from seized samples in 
the Bureau of Narcotics and Dangerous Drugs Laboratory in San 
Francisco all contained less than 1% THC. Samples from the State of 
California Bureau of Narcotic enforcement analyzed in our laboratory 
contained as little as 0.1% THC and a maximum of 0.9% * * * In a 
survey done in Ontario, Canada, Marshman and Gibbons found that of 
36 samples alleged to be marijuana with high cannabinoid content, 
34% contained no marijuana at all, and much of the rest was cut with 
other plant substances. A generous assumption is that marijuana 
generally available in the United States averages about 1.0% THC.

    It must be acknowledged that the THC content of domestically grown 
and imported marijuana has increased since these reports. However, the 
description by Weil, Zinberg & Nelson (1968), Agurell & Leander (1971), 
Jones (1971) and Barnett et al. (1982) highlight the historical 
importance of low THC concentrations contained in marijuana which 
provided the basis for the marijuana culture that developed in the 
1970s. The incident described by Jones was not an isolated case of the 
inadvertent misrepresentation of the THC content of marijuana extracts. 
Caldwell et al., (1969) found that the NIMH-supplied marijuana that 
they reported to have contained 1.3% THC was analyzed by two 
independent laboratories and found to contain as little as 0.2 to 0.5% 
THC. Similarly, according to Paton & Pertwee (1973) the THC content of 
material used by Clark & Nakashima (1968), Weil et al., (1968), Weil & 
Zinberg (1969), and Crancer et al., (1969) must be expected to be one-
third to one-sixth less than stated. This means that the positive 
results of all of these studies were the result of a surprisingly low 
THC-containing (1.0%) marijuana. The early scientific data on the 
subjective effects of marijuana were generated with these samples by 
experienced smokers smoking material in this potency range. These 
experienced marijuana smokers were reporting that these marijuana

[[Page 20061]]

samples were of ``average quality'' (Mechoulam, 1973).
    In an early study, Jones (1971) utilized 1 gram of plant material 
with a THC concentration of 0.9% (9 mg of THC). Experienced marijuana 
smokers were asked to freely smoke marijuana cigarettes for 10 minutes. 
The smoking topography of the smokers widely varied and was not 
controlled in this set of experiments. Subjects were asked to smoke the 
entire cigarette. Subjective state was measured by asking the subjects 
to make global estimates of his degree of intoxication on a 0-100 
scale. A score of 0 was defined as ``sober'' and a score of 100 as the 
most intoxicated or most ``stoned'' they had ever been in any social 
situation. At the end of the session (about 3 hrs), the subject also 
filled out a 272-item symptom checklist (SDEQ: subjective drug effects 
questionnaire) which taps some of the more unusual emotional, 
perceptual and cognitive effects produced by psychoactive drugs. The 
mean potency rating was 61 for the marijuana containing only 9 mg of 
THC. There was a tremendous range in the rating made by individual 
smokers. Jones concluded that the smokers may obtain intermittent 
reinforcement from THC but where much of the behavior and subsequent 
response is maintained by ``conditioned reinforcers'' such as the whole 
ritual of lighting up, the associated stimuli of smell, taste, visual 
stimuli and so on.
    Manno, Kiplinger, Haine, Bennett, & Forney (1970) asked subjects to 
smoke an entire 1 gram cigarette containing 1% THC (10 mg; low 
potency). The subjects were told to take 2 to 4 seconds to inhale and 
to hold the draw for 30 to 60 seconds. The expired smoke was collected 
and analyzed for THC content, as well. During the experiment the 
subjects smoked the entire cigarette; in all cases, less than 0.5 mg of 
THC remained in the residue of each cigarette. Manno et al. reported 
that the quantity of THC or other cannabinols present in a marijuana 
cigarette was not a reliable indicator of the amount of cannabinols 
that were delivered in the smoke of the cigarette. Controlled smoking 
experiments through a manufactured smoking machine demonstrated that 
approximately 50% of the \9\-THC originally present in the 
cigarette was delivered unchanged in the smoke. Manno et al. concluded 
that a dose of approximately 5 mg of \9\-THC was delivered 
which was estimated to be an administered dose in the range of 50 to 75 
g per kilogram. These low potency marijuana cigarettes 
produced significant motor and mental performance measures on the 
pursuit meter test, delayed auditory feedback, verbal output, reverse 
reading, reverse counting, progressive counting, simple addition, 
subtraction, addition +7, subtract +7, and color differentiation. These 
low potency cigarettes also produced significant pulse rate increases 
and significant increases on a somatic symptoms checklist. Unsolicited 
verbal comments from the subjects verified that the subjects were 
``high'' on these low potency marijuana cigarettes.
    Kiplinger, Manno, Rodda, Forney, Haine, Ease, & Richards (1971) 
conducted a randomized block, double-blind study designed to establish 
a dose-response analysis of the THC content in marijuana using a 
variety of behavioral and subjective effects measures. Marijuana 
cigarettes were manufactured to deliver doses of 0, 6.25, 12.5, 25, and 
50 g/kg of \9\-THC. Based on an average 70 kg man, 
the total delivered doses of THC were 0, 0.43, 0.875, 1.75, and 3.5 mg. 
Based on the assumption of a 50% loss of THC from pyrolysis and 
sidestream smoke these doses would be equivalent to smoking cigarettes 
containing 0, 0.08%, 0.16%, 0.3%, and 0.7% THC containing hemp. The 
lower concentrations of THC were used because these doses are found in 
the weaker ``hemp'' or fiber type marijuana commonly grown in the 
United States. All doses of THC, including the two lowest doses, 
increased the subjective ratings on both the ARCI and Cornell Medical 
Indexes, produced heart-rate increases, increased motoric decrements in 
pursuit meter, and produced decrements in mental performance using the 
delayed auditory feedback test. Most importantly, 80% of subjects 
correctly identified the lowest dose (6.25 g/kg; 0.43 mg THC) 
as active marijuana. The authors suggested that even lower doses might 
have measurable effects. Holtzman (1971) has suggested that one of the 
best predictors of a drug's abuse liability is the identification of 
the substance as ``drug-like'' by experienced drug users. The 
identification of the lowest dose of marijuana in the Kiplinger et al. 
and the other studies, discussed above, clearly suggests that 
industrial ``fiber-type'' marijuana has abuse potential.
    Many of the studies examining the behavioral effects of marijuana 
in animals have chosen to administer THC because of the difficulties in 
controlling and administering exact doses within and between subjects 
when using pyrolyzed forms of marijuana to animals. Accurate small-
animal smoke delivery systems are not yet available. The lack of water 
solubility of \9\-THC has made its administration and 
absorption a difficult problem for pharmacologists. Many different 
methods for suspending, solubilizing, or emulsifying \9\-THC 
have been used. None of these methods are without difficulty and 
without influence on absorption and pharmacological activity. The fact 
that many methods have been used by various investigators makes 
quantitative comparisons difficult.
    \9\-THC is the primary active ingredient of marijuana that 
produces the subjective ``high'' associated with smoking the plant 
material and is the chemical basis for cannabis abuse. Studies in 
several species of laboratory animals, including rhesus monkeys, rats 
and pigeons, have found pharmacological specificity for \9\-
THC at the cannabinoid receptors, and for cannabinoid drugs that bind 
with high affinity to brain cannabinoid receptors, and is psychoactive 
in humans and animals (Browne and Weissman, 1981; Balster and Prescott, 
1992; Compton et al., 1993; Wiley et al., 1995a,b). In general, the 
doses that produce its acute therapeutic effects and its cannabimimetic 
effects are similar (Devine et al., 1987; Consroe and Sandyk, 1992).

Central Nervous System Effects

    It has been reported that in man, doses above 1 milligram of 
\9\-THC absorbed by smoking marijuana are sufficient to cause 
a ``high'' (Agurell et al., 1986). Further, Agurell et al. (1986) 
suggested based on mouse data, that a pronounced ``high'' would be 
caused by the presence of as little as 10 micrograms of \9\-
THC in the brain, immediately after smoking a marijuana cigarette. 
These conclusions, based on a diverse array of pharmacokinetic studies, 
suggest that ``fiber-type'' marijuana clearly has the capacity to 
deposit these levels of THC into the brain of man soon after smoking a 
1% THC-containing marijuana cigarette (assuming the typical ``joint'' 
of 1 g, with 10mg THC). \9\-THC exerts its most prominent 
effects on the CNS and the cardiovascular system.
    Administration of \9\-THC via smoked cannabis is 
associated with decrements in motivation, cognition, judgement, memory, 
motor coordination, and alterations in perception (especially time 
perception), sensorium, and mood (cf., Jaffe, 1993). Most commonly 
\9\-THC produces an increase in well-being and euphoria 
accompanied by feelings of relaxation and sleepiness. The consequences 
produced by \9\-THC-induced behavioral impairments can greatly 
impact the public health and safety, given that individuals may be

[[Page 20062]]

attending school, working, or driving a motor vehicle under the 
influence of the drug (i.e., marijuana).
    Preclinical studies show that \9\-THC produces decrements 
in short-term memory, as evidenced by disruptions in acquisition and 
performance of maze behavior, conditioned emotional responses, and 
passive avoidance responses, impairment on the retention in delayed 
matching and alternation tests, and increases in resistance to 
extinction (Drew and Miller, 1974, Nakamura et al., 1991; Jaarbe and 
Mathis, 1992; Lichtman and Martin, 1996). Recent studies in rats found 
that these \9\-THC-induced impairments in spatial working 
memory were reversible after long abstinence (Nakamura et al., 1991) 
and can be blocked by the cannabinoid receptor antagonist SR141716A 
(Lichtman and Martin, 1996).
    Memory disturbances are one of the well-documented effects of 
``\9\-THC and marijuana on human behavior (Mendelson et al., 
1974; Jaffe, 1993; Hollister, 1986; Chait and Pierri, 1992). Clinical 
investigators of \9\-THC and marijuana's effects in memory 
have suggested that the drug produces a deficit in memory for recent 
events, and inhibition of the passage of memory from short-term to 
long-term storage (Drew and Miller, 1974; Darley 1973a,b).
    Heishman, Huestis, Henningfield, & Cone (1990) demonstrated 
cognitive performance decrements in marijuana smokers. Performance 
remained impaired on arithmetic and recall tests on the day after smoke 
administration. The authors suggested that performance decrements from 
smoking two to four marijuana cigarettes may be evident for 24 to 31 
hours. These data identify a particular set of performance decrements 
which characterize a marijuana-induced abstinence syndrome in man.

Cardiovascular Effects

    In humans, \9\-THC produces an increase in heart rate, an 
increase in systolic blood pressure while supine, decreases in blood 
pressure while standing, and a marked reddening of the conjunctivae 
(cf., Jaffe, 1993). The increase in heart rate is dose-dependent and 
its onset and duration varies but lags behind the peak of \9\-
THC levels in the blood.

Respiratory Effects

    Marijuana smoking produces inflammation, edema, and cell injury in 
the tracheobronchial mucosa of smokers and may be a risk factor for 
lung cancer (Sarafian et al., 1999). Smoke from marijuana has been 
shown to stimulate intermediate levels of reactive oxygen species. A 
brief, 30-minute exposure to marijuana smoke, regardless of the THC 
content, also induced necrotic cell death that increased steadily up to 
48 hours after administration. Sarafian et al., concluded that 
marijuana smoke containing THC is a potent source of cellular oxidative 
stress that could contribute significantly to cell injury and 
dysfunction in the lungs of smokers.
    The low incidence of carcinogenicity may be related to the fact 
that intoxication from marijuana does not require large amounts of 
smoked material. This may be especially true today since marijuana has 
been reported to be more potent now than a generation ago and 
individuals typically titrate their drug consumption to consistent 
levels of intoxication. However, several cases of lung cancer in young 
marijuana users with no have been reported (Fung et al., 1999).
    However, a recent study (Zhang et al., 1999, below) has suggested 
that marijuana use may dose-dependently interact with mutagenic 
sensitivity, cigarette smoking and alcohol use to increase the risk of 
head and neck cancer. THC is known to suppress macrophage natural 
killer cells and T-lymphocytes and reduce resistance to viral and 
bacterial infections. As shown below, Zhu et al., demonstrated that THC 
probably interacts with the T-cell cannabinoid CB2 receptor to produce 
these effects. As shown in the figure, below, these researchers found 
that THC promoted tumor growth in two immunocompetent mice lines. In 
two different weakly immunogenic murine lung cancer models, 
intermittent administration of THC led to accelerated growth of tumor 
implants compared with treatment with placebo alone. The immune 
inhibitory cytokines IL-10 and TGF-beta were augmented, while IFN-gamma 
was down-regulated at both the tumor site and in the spleens of THC-
treated mice. This has been the first clear demonstration that THC 
promotes tumor growth and supports the epidemiological evidence of an 
increased risk of cancer among marijuana smokers.
    In a recent comprehensive review of the existing literature base, 
Carriot & Sasco (2000) reported that users under the age of 40 years of 
age were more susceptible to squamous-cell carcinoma of the upper 
aerodigestive tract, particularly of the tongue and larynx, and 
possibly the lung. Others tumors being suspected are non-lymphoblastic 
acute leukemia and astrocytoma. In head and neck cancer carcinogenicity 
was observed for regular (i.e. more than once a day for years) cannabis 
smokers. Moreover, cannabis increases the risk of head and neck cancer 
in a dose-response manner for frequency and duration of use. THC seems 
to have a specific carcinogenic effect different from that of the 
pyrolysis products produced by (nicotine) cigarette smoking.
(3) The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance
    In general, the petitioner argues that the chemistry, toxicology 
and pharmacology of marijuana has been subjected to extensive study and 
peer review, and have been well characterized in the scientific 
literature. In addition, the discovery of the cannabinoid receptor has 
shed new light on the effects of marijuana and its mechanism of action.
    The literature cited by the petitioner (Tashkin et al., 1987, 1988, 
1990, 1991, 1993; Barbers et al., 1991; Sherman et al., 1991a, 1991b; 
Wu et al., 1992) provide data about the effects of marijuana smoke on 
the lungs, which, by the petitioner's own admission, is inherently 
unhealthy. Data show that smoking marijuana is associated with more tar 
than cigarettes and holding your breath (a common practice of marijuana 
smokers) increases carbon monoxide concentration. His assertion that 
Schedule I policy makes promoting safer marijuana smoking habits 
impossible has no basis in law (exact citations are found in petition).
    Pulmonary effects of smoked marijuana include bronchodilation after 
acute exposure. Chronic bronchitis and pharyngitis are associated with 
repeated pulmonary illness. With chronic marijuana smoking, large 
airway obstruction and cellular inflammatory abnormalities appear in 
bronchial epithelium (Adams and Martin, 1996). Chronic marijuana use is 
associated with the same types of health problems as cigarette smoking: 
increased frequency of bronchitis, emphysema and asthma. The ability of 
alveolar macrophages to inactivate bacteria in the lung is impaired. 
Local irritation and narrowing of airways also contribute to problems 
in these patients.
    Work by Perez-Reyes et al. (1991) and Agurell et al. (1989) 
provides data about the pharmacokinetics of THC from smoked marijuana.
    When marijuana is smoked, THC in the form of an aerosol in the 
inhaled smoked is absorbed within seconds and delivered to the brain 
rapidly and efficiently. Peak venous blood levels 75-150 ng/ml usually 
occur by the end of smoking a cigarette and level of THC

[[Page 20063]]

in the arterial system is probably much higher (Agurell et al., 1986).
    Toxicity by definition is the ability of an agent to produce injury 
or cause harm (morbidity/mortality). It is not clear that the effects 
of marijuana use are ``well-established,'' but what is known about the 
psychoactive effects, lung effects, endocrine effects etc. would 
suggest that smoking marijuana is not benign.
    The cardiovascular effects of smoked or oral marijuana have not 
presented any health problems for healthy and relatively young users. 
However, marijuana smoking by older patients, particularly those with 
some degree of coronary artery disease, is likely to pose greater risks 
because of the resulting increased cardiac work, increased 
catecholamines, carboxyhemoglobin and postural hypotension (Benzowitz 
and Martin, 1996; Hollister, 1988).
    The endocrine system effects include moderate depression of 
spermatogenesis and sperm motility and decrease in plasma testosterone 
on males. Prolactin, FSH, LH, and GH levels are decreased in females 
(Mendelson and Mello, 1984). Relatively little study has been done on 
human female endocrine or reproductive function.
    THC and other cannabinoids in marijuana have immunosuppressant 
properties producing impaired cell-mediated and humoral immune system 
responses. THC and other cannabinoids suppress antibody formation, 
cytokine production, leukocyte migration and killer-cell activity 
(Adams and Martin, 1996).
    Marijuana may cause membrane perturbations in cells. At the 
marijuana conference in July, 1995 sponsored by NIH, NIDA and DHHS, Dr. 
Cabral stated that THC effects body functions by accumulating in fatty 
tissue. While a receptor-based mechanism of action has been determined, 
localized and characterized it is not clear that this necessarily 
negates membrane (high fatty acids) effects.
    Mechanisms for marijuana's psychoactive effects were thought to be 
through interactions of the lipid component of cell membranes. The 
discovery of the cannabinoid receptor has changed that thinking and it 
is now believed that most of the effects of marijuana are mediated 
through cannabinoid receptors. Receptors are located in brain areas 
concerned with memory, cognition and motor coordination. An endogenous 
ligand, anandamide, has been identified but not studied in humans 
(Thomas et al. 1996). A specific THC antagonist, SR141716A, produces 
intense withdrawal signs and behaviors in rodents that have been 
exposed to THC for even a relatively short period of time (Adams and 
Martin, 1996). Clinical pharmacology of the antagonist has not been 
studied in humans.
    Most of what is known about human pharmacology of smoked marijuana 
comes from experiments with plant material containing about 2 percent 
THC or less. Very few controlled studies have been done with elderly, 
inexperienced or unhealthy users and data suggest that adverse effects 
may differ from healthy volunteers (Hollister 1986, 1988).
    Most of what is written about the pharmacological effects of 
marijuana is inferred from experiments on pure THC. The amount of 
Cannabidiol and other cannabinoids in smoked marijuana could modify the 
effects of THC.
    Tolerance to marijuana's psychoactive effect probably results from 
down regulation of cannabinoid receptors which is a form of 
desensitization of neuronal cells. In general, tolerance to marijuana's 
effects is often associated with an increased dependence liability. 
Data indicate that people escalate the amount of marijuana they smoke 
and continue to use marijuana despite negative consequences. These are 
classic signs of developing dependence.
    After repeated smoked or oral marijuana doses, marked tolerance is 
rapidly acquired to many of marijuana's effects: cardiovascular, 
autoimmune and many subjective effects. After exposure is stopped, 
tolerance is lost with similar rapidity (Jones et al., 1981)
    Withdrawal symptoms and signs appearing within hours after 
cessation of repeated marijuana use have been reported in clinical 
settings (Duffy and Milan, 1996; Mendelson et al., 1984). Typical 
symptoms and signs were restlessness, insomnia, irritability, 
salivation, diarrhea, increased body temperature and sleep disturbances 
(Jones et al., 1981).
    Data on the immune system indicates that marijuana does effect the 
body's ability to resist microbes including bacteria, viruses and fungi 
and decreases the body's antitumor activity. THC effects macrophages, 
T-lymphocytes and B-lymphocyts. A THC receptor has been found in the 
spleen. These effects may be receptor mediated. In a person with 
compromised immune function marijuana could pose a health risk.
    Acute effects of transient anxiety, panic, feelings of depression 
and other dysphoric moods have been reported by 17 percent of regular 
marijuana users in a large study (Tart, 1971). Whether marijuana can 
produce lasting mood disorders or schizophrenia is less clear (IOM, 
1982). Chronic marijuana use can be associated with behavior 
characterized by apathy and loss of motivation along with impaired 
educational performance (Pope and Yurgelun-Todd, 1996).
    DEA has found that since HHS's last medical and scientific 
evaluation on marijuana (1986), there have been a significant number of 
new findings relating to THC:
    1. Cannabinoid receptors have been identified in the brain and 
spleen;
    2. The CNS cannabinoid receptor has been cloned;
    3. An endogenous arachidonic acid derivative ligand (anandamide) 
has been identified;
    4. A high density of cannabinoid receptors have been located in the 
cerebral cortex, hippocampus, striatum and cerebellum; and
    5. An antagonist to the cannabinoid receptor has been developed
    In addition, a significant body of literature has been amassed 
regarding the effects of marijuana.
    For example:
    1. Studies on the acute and chronic effects of marijuana on the 
endocrine system;
    2. Effect of marijuana on learning and memory;
    3. Effect of marijuana on pregnant females and their offspring 
development;
    4. Effect on the immune system;
    5. Effect on the lungs; and
    6. Effects of chronic use with regard to tolerance, dependence and 
``amotivational syndrome.''
    While many of the petitioner's arguments are based on new research 
findings, the interpretation of those findings requires clarification.
    As was pointed out by the NIH expert committee on the medical 
utility of marijuana, marijuana is not a single drug. It is a variable 
and complex mixture of plant parts with a varying mix of biologically 
active material. Characterizing the clinical pharmacology is difficult 
especially when the plant is smoked or eaten. Some of the inconsistency 
or uncertainty in scientific reports describing the clinical 
pharmacology of marijuana results from the inherently variable potency 
of the plant material. Inadequate control over drug dose together with 
the use of research subjects with variable experience in using 
marijuana contributes to the uncertainty about what marijuana does or 
does not do.
    There are studies in the scientific literature that have evaluated 
dose-related subjective and reinforcing effects of Cannabis sativa in 
humans. These

[[Page 20064]]

studies have assessed the subjective and reinforcing effects of 
cannabis cigarettes containing different potencies of THC and/or which 
have manipulated the THC dose by varying the volume of THC smoke 
inhaled (Azorlosa et al., 1992; Lukas et al., 1995; Chait et al., 1988; 
Chait and Burke, 1994; Kelly et al., 1993; Kipplinger et al, 1971, 
Manno et al., 1970).
    Chait et al. (1988) studied the discriminative stimulus effects of 
smoked marijuana cigarettes containing THC contents of 0%, 0.9%, 1.4%, 
2.7%. Marijuana smokers were trained to discriminate smoked marijuana 
from placebo using 4 puff of a 2.7%-THC cigarettes. Subjective ratings 
of ``high'', mean peak ``high'' scores, and physiological measures 
(i.e., heart rate) were significantly and dose-dependently increased 
after smoking the 0.9%, 1.4%, 2.7%. Marijuana cigarettes containing 
1.4% THC completely substituted for 2.7%-THC on drug identification 
tasks, however, 0.9%-THC did not. The authors found that the onset of 
discriminative stimulus effects was within 90 seconds after smoking 
began (after the first two puffs). Since the 1.4%-THC cigarette 
substituted for 2-puffs of the 2.7%-THC cigarette, the authors estimate 
that an inhaled dose of THC as low as 3 mg can produce discriminable 
subjective effects.
    Similarly, Lukas et al. (1995) reported that marijuana cigarettes 
containing either 1.26% or 2.53% THC produced significant and dose-
dependent increases in level of intoxication and euphoria in male 
occasional marijuana smokers. Four of the six subjects that smoked the 
1.26%-THC cigarette reported marijuana effects and 75% of these 
subjects reported euphoria. All six of the subjects that smoked 2.53% 
THC reported marijuana effects and euphoria. Peak levels of self-
reported intoxication occurred at 15 and 30 minutes after smoking and 
returned to control levels by 90-105 minutes. There was no difference 
between latency to or duration of euphoria after smoking either the 
1.26% or 2.53% THC cigarettes. The higher dose-marijuana cigarette 
produced a more rapid onset and longer duration of action than the 
lower dose marijuana cigarette (1.26% THC). Plasma THC levels peaked 5-
10 minutes after smoking began; the average peak level attained after 
the low- and high-dose marijuana cigarette was 36 and 69 ng/ml 
respectively.
    In order to determine marijuana dose-effects on subjective and 
performance measures over a wide dose range, Azorlosa et al. (1992) 
evaluated the effects of 4, 10, or 25 puffs from marijuana cigarettes 
containing 1.75 or 3.55% THC in seven male moderate users of marijuana. 
Orderly dose-response curves were produced for subjective drug effects, 
heart rate, and plasma concentration, as a function of THC content and 
number of puffs. After smoking the 1.75% THC cigarette, maximal plasma 
THC levels were 57 ng/ml immediately after smoking, 18.3 ng/ml 15 
minutes after smoking, 10.3 ng/ml 30 minutes after smoking, and 7.7 ng/
ml 45 minutes after smoking.
    The study also show that subjects could smoke more of the low THC 
cigarette to produced effects that were similar to the high THC dose 
cigarette (Azorlosa et al., 1992). There were nearly identical THC 
levels produced by 10-puff low-THC cigarette (98.6 ng/ml) and 4-puff 
high THC cigarette (89.4 ng/ml). Similarly, the subjective effects 
ratings, including high, stoned, impaired, confused, clear-headed and 
sluggish, produced under the 10 puff low- and high-THC and 25 puff low-
THC conditions did not differ significantly from each other.
    As with most drugs of abuse, higher doses of marijuana are 
preferred over lower dose. Although not preferred, these lower doses 
still produce cannabimimetic effects. Twelve regular marijuana smokers 
participated in a study designed to determine the preference of a low 
potency (0.64%-THC) vs. a high potency (1.95%-THC) marijuana cigarette 
(Chait and Burke, 1994). The subjects first sampled the marijuana of 
two different potencies in one session, then chose which potency and 
how much to smoke. During sampling sessions, there were significant 
dose-dependent increases in heart rate and subjective effects, 
including ratings of peak ``high'', strength of drug effects, 
stimulated, and drug liking. During choice sessions, the higher dose 
marijuana was chosen over the lower dose marijuana on 87.5% of 
occasions. Not surprising, there was a significant positive correlation 
between the total number of cigarettes smoked and the ratings of 
subjective effects, strength of drug effect, drug ``liking'', expired 
air carbon monoxide, and heart rate increases. The authors state it is 
not necessary valid to assume that the preference observed in the 
present study for the high-potency marijuana was due to greater CNS 
effects from its higher THC content. The present study found that the 
low- and high-potency marijuana cigarettes also differ on several 
sensory dimensions; the high-potency THC was found to ``fresher'' and 
``hotter''. Other studies found that marijuana cigarettes containing 
different THC contents varied in sensory dimensions (cf., Chait et al., 
1988; Nemeth-Coslett et al., 1986).
    As described above in Factors 1 and 2, there are data to show that 
the effects of THC are dose-dependent and several studies have found 
that low-potency THC is behaviorally active and can produce 
cannabimimetic-like subjective and physiological effects. Preclinical 
and clinical experimental data demonstrate that marijuana and 
9-THC have similar abuse liabilities (i.e., drug 
discrimination, self-administration, subjective effects). Both 
preclinical and clinical studies show that discontinuation of either 
marijuana and 9-THC administration produces a mild 
withdrawal syndrome. Most of what is known about human pharmacology of 
smoked marijuana comes from experiments with plant material containing 
about 2-3% percent THC or less, in cigarette form provided by NIDA 
(cf., NIDA, 1996). Very few controlled studies have been done with 
elderly, inexperienced or unhealthy users and data suggests that 
adverse effects may differ from healthy volunteers (Hollister 1986, 
1988).
    Cannabidiol (CBD) does not have psychotomimetic properties and does 
not appear to produce a subjective ``high'' in human subjects (Musty, 
1984). This does not mean that CBD does not have CNS effects or that it 
does not contribute to the subjective high produced by the 
cannabinoids. CBD has been clearly shown to have anti-convulsant 
effects as demonstrated by several techniques such as electroshock-
induced seizures, kindled seizures, pentylenetetrazole-induced seizures 
(Carlini et al., 1973; Izquierdo & Tannhauser, 1973). The suggestion 
that CBD does not have abuse liability is based in part on the findings 
that CBD does not produce THC-like discriminative stimulus effects in 
animals (Ford, Balster, Dewey, Rosecrans, & Harris, 1984; but see 
below). However, these tests were conducted with CBD administered alone 
and at only one or two time-points (however, see Jarbe below). The 
normal route of administration of THC and CBD in humans is by smoking. 
This mode of administration provides a variable proportion of 
cannabinoid ratios to the individual subject. As stated above, the 
chemistry of marijuana is not just the chemistry of 
9-THC , but at a minimum, a combination of 
cannabinoids. According to Turner (1980) kinetic interactions have been 
reported to occur among the cannabinoids since the early 1970s. Control 
studies with varying ratios of cannabinoid administrations and

[[Page 20065]]

complete time-effect functions have still not been conducted.
    Domino, Domino, & Domino (1984) have shown that the rate-of-change 
of the subjective high after marijuana administration does not follow 
the rate-of-change of plasma or brain THC levels. While plasma THC 
function show a sharp ascending limb and exponential decline after 
administration, the subjective ``high'' peaks after the peak in THC and 
shows a protracted slow decline. The proportional ratios between the 
cannabinoids and their metabolites in inhaled marijuana, acting as 
entourage substances, may have emergent properties that cannot be 
ascribed to any one component of the complex stimulus administered in 
the smoke (Gauvin & Baird, 1999). These cannabinoid ratios may play a 
critical role in the initiation, maintenance, and relapse of marijuana 
smoking.
    CBD has been clearly shown to have anxiolytic (Guimares et al, 
1990, 1994; Musty, 1984; Onaivi, Green, & Martin, 1990; Zuardi et al., 
1982) and antipsychotic (Zuardi et al., 1995; Zuardi, Antunes 
Rodrigues, & Cunha, 1991) effects in both animal and man. In the sense 
that many studies which have examined the subjective profiles of 
marijuana have demonstrated an ``anxiety'' component to THC and 
marijuana use, it should not be surprising that CBD's anxiolytic 
effects block some of these discriminative properties. However, it 
should not be concluded from these results that CBD's anxiolytic 
properties do not have or cannot acquire reinforcing efficacy. It has 
been suggested that the affective baseline of the drug abuser plays a 
critical role in the stimulus properties of drugs (Gauvin, Harland, & 
Holloway, 1989). The anxiolytic properties of CBD may serve to diminish 
the anxiety states associated with many psychopathological states, thus 
effectively functioning as a ``negative reinforcer''. As such, CBD may 
function to increase the likelihood of its administration by its 
ability to remove the negative affective states in anxious patients. A 
number of authors have summarized the process by which marijuana 
smokers ``learn to get high'' (cf. Jones, 1971, 1980; Cappell & Pliner, 
1974). Karniol et al., (1974) have clearly demonstrated that the co-
administration of CBD with THC actually blocks the anxiety induced by 
9-THC, leaving the subjects less tense and 
potentiating the reinforcing effects of the THC as demonstrated by the 
subjects verbal reports of enjoying the experience even more. Very few 
experienced marijuana smokers report symptoms of anxiety (cf Jones, 
1971, 1980; Petersen, 1980). The relief of the anxiety and/or 
psychotomimetic properties of THC by the co-administration of CBD may 
effectively function as a ``negative reinforcer'', increasing the 
likelihood of continued abuse.
    Other studies have reported that cannabidiol has cannabinoid 
properties, including anticonvulsant effects in animal and human models 
(Consroe et al., 1981; Carlini et al., 1981; Doyle and Spence, 1995), 
hypnotic effects (Monti et al., 1977), and rate-decreasing effects on 
operant behavior (Hiltunen et al., 1988). Experiments with cannabidiol 
in combination with THC have found that certain behavioral responses 
induced by THC (i.e., operant, schedule-controlled responding) were 
attenuated by cannabidiol (Borgen and Davis, 1974; Brady and Balster, 
1980; Consroe et al., 1977; Dalton et al., 1976; Karniol and Carlini, 
1973; Karniol et al., 1974; Welburn et al., 1976; Zuardi and Karniol, 
1983; Zuardi et al., 1981, 1982; Hiltunen et al., 1988). However, other 
affects produced by THC are augmented or prolonged by the combined 
administration of CBD and THC or marijuana extract (Chesher and 
Jackson, 1974; Hine et al., 1975a,b; Fernandes et al., 1974; Karniol 
and Carlini, 1973; Musty and Sands, 1978; Zuardi and Karniol, 1983; 
Zuardi et al., 1984). Still other studies did not report any behavioral 
interaction between the CBD and THC (Bird et al., 1980; Browne and 
Weissman, 1981; Hollister and Gillespie, 1975; Jarbe and Henricksson, 
1974; Jarbe et al., 1977; Mechoulam et al., 1970; Sanders et al., 1979; 
Ten Ham and DeLong, 1975).
    A study to characterize the interaction between CBD and THC was 
conducted using preclinical drug discrimination procedures. Rats and 
pigeons trained to discriminate the presence or absence of THC, and 
tested with CBD administered alone and in combinations with THC 
(Hiltunen and Jarbe, 1986). Specifically, in rats trained to 
discriminate 3.0 mg/kg, i.p. THC, CBD (30.0 mg/kg) was administered 
alone and in combination with THC (0.3 and 1.0 mg/kg, i.p.). In pigeons 
trained to discriminate 0.56 mg/kg, i.m. THC, CBD (17.5 mg/kg) was 
administered alone and in combination with THC (0.1, 0.3, and 0.56 mg/
kg, i.m.). CBD prolonged the discriminative stimulus effects of THC in 
rats, but did not change the time-effect curve for THC in pigeons. In 
pigeons, the administration of CBD did not produce any differential 
effect under a fixed ratio schedule of reinforcement (Hiltunen and 
Jarbe, 1986).
    These data suggest that CBD may somehow augment or prolong the 
actions of THC in rats and had no effect in pigeons. In the present 
study, the CBD/THC ratios ranged from 30:1 to 100:1 in rats and 
enhanced the stimulus effects of THC. However, similar CBD/THC ratios 
in pigeons (31:1, 58:1 and 175:1) did not result in any changes to 
THC's discriminative stimulus or response rate effects (Hiltunen and 
Jarbe, 1986).
    In conclusion, although cannabidiol does contribute to the other 
effects of cannabis, it appears to lack cannabimimetic properties. In 
addition, there does not appear to be a scientific consensus that 
cannabidiol pharmacologically antagonizes, in a classic sense, the 
effects of THC. Certain functional blockades have been demonstrated. As 
presented in the scientific literature cited above, the ability of 
cannabidiol to modify the effects of THC may be specific to only some 
effects of THC. Most importantly, CBD appears to potentiate the 
euphorigenic and reinforcing effects of THC which suggests that the 
interaction between THC and CBD is synergistic and may actually 
contribute to the abuse of marijuana.
(4) Its History and Current Pattern of Abuse
    The federal databases documenting the actual abuse of marijuana are 
distributed and maintained by the HHS, therefore, we acknowledge and 
concur with HHS's review of this factor analysis.
(5) The Scope, Duration, and Significance of Abuse
    The basis of the petition to remove marijuana from Schedules I and 
II is not based on data required by 21 U.S.C. 811 (c) (i.e., the scope, 
duration, and significance of use of the substances).
    The petitioner seems to assume that the concept, use of an illegal 
substance is abuse of that substance, is a concept which is universally 
held to the exclusion of any other definition of abuse of a substance. 
While this concept is valid in general terms because marijuana is not a 
legitimately marketed product therefore it has no legitimate use, 
holding that all adhere to this definition of abuse denigrates the 
intellectual capacity of all researchers who investigate the topic. The 
petitioner neglects to recognize the efforts of the DHHS and many 
groups which expend a great deal of time and money in research efforts 
directed toward developing and implementing drug-abuse prevention 
programs. The petitioner also rejects the notion that there are 
individuals who abuse marijuana even though the National Household 
Survey, to which the

[[Page 20066]]

petitioner refers, would indicate that is the case.
    It has not been established that marijuana is effective in treating 
any medical condition. (NIH Workshop on the Medical Utility of 
Marijuana, 1997) At this time, there is no body of knowledge to which a 
physician can turn to learn which medical condition in which patient 
will be ameliorated at which dosage schedule of smoked marijuana nor 
can he/she determine in which patient the benefits will exceed the 
risks associated with such treatment. The petitioner, therefore, is 
advocating that individuals become their own physicians, a notion that 
even primitive man found unsatisfactory.
    There is nothing absolute in the placement of a substance into a 
particular CSA schedule. The placement of a substance in a CSA schedule 
is the government's mechanism for seeing that the availability of 
certain psychoactive substances is limited to the industrial, 
scientific and medical needs which are accepted as being legitimate. 
The placement of a substance into Schedule I does not preclude research 
of that substance, nor does it preclude development of a marketable 
product. The National Institute on Drug Abuse, an element of the 
Department of Health and Human Services, convened a conference in 1995 
and with NIDA's parent organization, the National Institutes of Health, 
assembled an ad hoc group of experts in 1997 to address issues related 
to the use, abuse, and medical utility of marijuana. With regard to the 
medical utility of marijuana, the experts concluded that the scientific 
process should be allowed to evaluate the potential therapeutic effects 
of marijuana for certain disorders, dissociated from the societal 
debate over the potential harmful effects of nonmedical marijuana use. 
All decisions on the ultimate usefulness of a medical intervention are 
based on a benefit/risk calculation, and marijuana should be no 
exception to this generally accepted principle.
    The cause and effect relationship which the petitioner poses is 
neither substantiated nor relevant. Estimates are useful when 
attempting to allocate resources but they are not necessary for 
effective eradication of marijuana. Each year, millions of plants are 
destroyed before their product reaches the market. In addition, federal 
law enforcement activities result in the seizure of another million or 
more pounds of product annually.
    As reviewed by Gledhill, Lee, Strote, & Wechsler (2000), rates of 
illicit drug use, especially marijuana, have risen uniformly among the 
youth in the United States in the past decade and remained steady at 
the end of the 1990s despite efforts to reduce prevalence. Between 1991 
and 1997, rates of past 30-day marijuana use had more than doubled 
among U.S. 10th grade secondary school students and more than tripled 
among seniors, after a decade of decline. Between 1997 and 1999, rates 
of marijuana use among secondary school students declined for the first 
time in the 1990s mainly among the older students (16-17 yrs old).
    Disturbing are the findings that marijuana use is steadily 
increasing among 8th, 10th and 12th graders at all prevalence levels. 
According to the 1996 survey results from the Monitoring the Future 
Study, 45% of seniors and 35% of 10th graders claimed to have used 
marijuana at least once. Among eighth graders, annual prevalence rates 
more nearly tripled 1992 to 1996. Accompanying the increased use of 
marijuana among High School seniors is a decreasing perceived risk or 
harm of marijuana use (Johnston et al., 1996). In reality, the harm 
associated with the abuse of marijuana is increasing; the marijuana 
emergency room and treatment admission rates continue to increase in 
recent years.
    Gledhill-Hoyt, Lee, Strote, & Wechsler (2000) examined rates and 
patterns of marijuana use among different types of students and 
colleges in 1999, and changes in use since 1993. 15,403 students in 
1993, 14,724 students in 1997, and 14,138 students in 1999 were 
assessed. The prevalence of past 30-day and annual marijuana use 
increased in nearly all student demographic subgroups, and at all types 
of colleges. Nine out of 10 students (91%) who used marijuana in the 
past 30 days had used other illicit drugs, smoked cigarettes, and/or 
engaged in binge drinking. Twenty-nine percent of past 30-day marijuana 
users first used marijuana and 34% began to use marijuana regularly at 
or after the age of 18, when most were in college.
    Coffey, Lynskey, Wolfe, & Patton (2000) examined predictors of 
cannabis use initiation, continuity and progression to daily use in 
adolescents. Over 2,000 students were examined. Peer cannabis use, 
daily smoking, alcohol use, antisocial behavior and high rates of 
school-level cannabis use were associated with middle-school cannabis 
use and independently predicted high-school uptake. Cannabis use 
persisted into high-school use in 80% of all middle-school users. 
Middle-school use independently predicted incidents in high-school 
daily use in males, while high-dose alcohol use and antisocial behavior 
predicted incidence of daily use in high school females. The authors 
also found that cigarette smoking was an important predictor of both 
initiation and persisting cannabis use.
    Farrelly et al., (2001) reviewed the NHSDA from 1990 through 1996 
and compared those statistics with State law enforcement policies and 
prices that affect marijuana use in the general public. These authors 
found evidence that both higher fines for marijuana possession and 
increased probability of arrest decreased the probability that a young 
adult will use marijuana. These new data refute the petitioner's 
suggestion that legal control of marijuana does not have a dampening 
effect on its use.
(6) What, if any, Risks are There to Public Health
    There are human data demonstrating that marijuana and 
9-THC produce an increase in heart rate, an 
increase in systolic blood pressure while supine, and decreases in 
blood pressure while standing (cf., Jaffe, 1993). The increase in heart 
rate is dose-dependent and its onset and duration correlate with levels 
of 9-THC in the blood.
    When DEA evaluates a drug for control or rescheduling, the question 
of whether the substance creates dangers to the public health, in 
addition to, or because of, its abuse potential must be considered. A 
drug substances' risk to the public health manifests itself in many 
ways. Abuse of a substance may affect the physical and/or psychological 
functioning of an individual abuser. In addition, it may have 
disruptive effects on the abuser's family, friends, work environment, 
and society in general. Abuse of certain substances leads to a number 
of antisocial behaviors, including violent behavior, endangering 
others, criminal activity, and driving while intoxicated. Data examined 
under this specific factor of the CSA ranges from preclinical toxicity 
to postmarketing adverse reactions in humans. DEA reviews data from 
many sources, including forensic laboratory analyses, crime 
laboratories, medical examiners, poison control centers, substance 
abuse treatment centers, and the scientific and medical literature.
    Adverse effects associated with marijuana and THC as determined by 
clinical trials, FDA adverse drug effects and World Health Organization 
data, are described elsewhere (cf., Chait and Zacny, 1988; Chait and 
Zacny, 1992; Cone et al., 1988; and Pertwee, 1991). A recent press 
release from the Substance Abuse and Mental Health Service 
Administration reported that adolescents, age 12 to 17, who use

[[Page 20067]]

marijuana weekly are nine times more likely than non-users to 
experiment with illegal drugs or alcohol; six times more likely to run 
away from home; five times more likely to steal; nearly four times more 
likely to engage in violence; and three times more likely to have 
thoughts about committing suicide. It was also reported that 
adolescents also associated social withdrawal, physical complaints, 
anxiety, and depression, attention problems, and thoughts of suicide 
with past-year marijuana use (SAMHSA, 1999). Budney, Novy, & Hughes 
(1999) have recently examined the withdrawal symptomology in chronic 
marijuana users seeking treatment for their dependence. The majority of 
the subjects (85%) reported that they had experienced symptoms of at 
least moderate severity and 47% experienced greater than four symptoms 
rated as severe. The most reported mood symptoms associated with the 
withdrawal state were irritability, nervousness, depression, and anger. 
Some of the behavioral characteristics of the marijuana withdrawal 
syndrome were craving, restlessness, sleep disruptions, strange dreams, 
changes in appetite, and violent outbursts. These data clearly support 
the validity and clinical significance of a marijuana withdrawal 
syndrome in man.

Toxic Effects of Marijuana and THC

    Although a median lethal dose (LD50) of THC has not been 
established in humans, it has been found in laboratory animals 
(Phillips et al., 1971). In mice, the LD50 for THC was 
481.9, 454.9 and 28.6 mg/kg after oral, intraperitoneal, and 
intravenous routes of administration. In rats, the LD50 for 
THC (extracted from marijuana) was 666.0, 372.9 and 42.5 mg/kg after 
oral, intraperitoneal, and intravenous routes of administration. 
Another study examined the toxicity of THC in rats, dogs and monkeys 
(Thompson et al., 1972). Similarly this study found that in rats, the 
LD50 for THC was 1140.0, 400.0 and 20.0 mg/kg after oral, 
intraperitoneal, and intravenous routes of administration. There was no 
LD50 attained in monkeys and dogs by the oral route. Over 
3000 mg/kg of THC was administered without lethality to dogs and 
monkeys. A dose of about 1000 mg/kg was the lowest dose that caused 
death in any animal. Behavioral changes in the survivors included 
sedation, huddled postures, muscle tremors, hypersensitivity to sound 
and immobility.
    The cause of death in the rats and mice after oral THC was profound 
depression leading to dyspnea, prostration, weight loss, loss of 
righting reflex, ataxia, and severe decreases in body temperature 
leading to cessation of respiration from 10 to 40 hours after a single 
oral dose (Thompson et al., 1972). No consistent pathologic changes 
were observed in any organs. The cause of death in dogs or monkeys 
(when it rarely occurred) did not appear to be via the same mechanism 
as in the rats.
    In humans, the estimated lethal dose of intravenous dronabinol 
[(-)-\9\-THC] is 30 mg/kg (2100 mg/70 kg). In antiemetic 
studies, significant CNS symptoms were observed following oral doses of 
0.4 mg/kg (28 mg/70 kg) (PDR, 1997). Signs and symptoms of mild 
dronabinol intoxication include drowsiness, euphoria, heightened 
sensory awareness, altered time perception, reddened conjunctiva, dry 
mouth and tachycardia. Following moderate dronabinol intoxication 
patients may experience memory impairment, depersonalization, mood 
alterations, urinary retention, and reduced bowel motility. Signs and 
symptoms of severe dronabinol intoxication include decreased motor 
coordination, lethargy, slurred speech, and postural hypotension. 
Dronabinol may produce panic reactions in apprehensive patients or 
seizures in those with an existing seizure disorder (PDR, 1997).
    Thus, large doses of THC ingested by mouth were not often 
associated with toxicity in dogs, nonhuman primates and humans. 
However, it did produce fatalities in rodents as a result of profound 
CNS depression. Thus, the evidence from studies in laboratory animals 
and human case reports indicates that the lethal dose of THC is quite 
large. The adverse effects associated with THC use are generally 
extensions of the CNS effects of the drug and are similar to those 
reported after administration of marijuana (cf., Chait and Zacny, 1988; 
Chait and Zacny, 1992; Cone et al., 1988; and Pertwee, 1991).

Health and Safety Risks of \9\-THC Use

    The recent Institute of Medicine report on the scientific basis for 
the medicinal use of cannabinoid products stated the following:

    Not surprisingly, most users of other illicit drugs have used 
marijuana first. In fact, most drug users begin with alcohol and 
nicotine before marijuana--usually before they are of legal age. In 
the sense that marijuana use typically precedes rather than follows 
initiation of other illicit drug use, it is indeed a ``gateway'' 
drug (Institute of Medicine Report 1999, p. ES.7).

    Golub and Johnson (1994) examined the developmental pathway 
followed by a sample of persons who became serious drug abusers. Of the 
837 persons sampled 84% had onset to more serious drugs by the time of 
the interviews. Most of the sample reported having used marijuana 
(91%). Two-thirds of the drug abusers reported having used marijuana 
prior to onset to more serious drugs and an additional 19% reported 
having onset to marijuana and more serious drugs in the same year. 
These data strongly suggest that marijuana does plan an important role 
on the pathway to more serious drugs use. Further, the proportion who 
onset to marijuana before or in the same year as more serious drugs was 
reported to have increased substantially with time from a low of 78% 
for persons born from 1928 to 1952 to 95% for the most recent birth 
cohort of the study (1968-1973). These findings further suggest that 
marijuana's role as a gateway to more serious substance sue has become 
more pronounced over time.
    Ferguson & Horwood (2000) have examined the relationship between 
cannabis use in adolescence and the onset of other illicit drug use. 
Data were gathered over the course of a 21 year longitudinal study of a 
birth cohort of 1,265 children. By the age of 21, just over a quarter 
of this cohort reported using various forms of illicit drugs on at 
least one occasion. In agreement with the predictions of a ``stage-
theory'' of the ``gateway hypothesis'' there was strong evidence of a 
temporal sequence in which the use of cannabis preceded the onset of 
the use of other illicit drugs. Of those reporting the use of illicit 
drugs, all but three (99%) had used cannabis prior to the use of other 
illicit drugs. However, the converse was not true and the majority 
(63%) of those using cannabis did not progress to the use of other 
forms of illicit drugs. In addition, to these findings there was a 
strong dose-response relationship between the extent of cannabis use 
and the onset of illicit drug use. The analysis suggested that those 
using cannabis in any given year on at least 50 occasions had hazards 
of using other illicit drugs that were over 140 times higher than those 
who did not use in the year. Furthermore, hazards of the onset of other 
illicit drug use increased steadily with increasing cannabis use. The 
very strong gradient in risk reflected the facts that: (1) Among non-
users of cannabis the use of other forms of illicit drugs was almost 
non-existent and (2) among regular users of cannabis the use of other 
illicit drugs was common. To address the issue of ``confounding 
factors'', the associations between cannabis use and the onset of 
illicit drug use were adjusted for a series of

[[Page 20068]]

prospectively measured confounding factors that included measures of 
social disadvantage, family functioning, parental adjustment, 
individual characteristics, attitudes to drug use and early adolescent 
behavior. After adjustments for these factors, there was still evidence 
of strong dose-response relationships between the extent of cannabis 
use in a given year and the onset of illicit drug use--the hazards of 
the onset of illicit drug use was 100 times those of non-users.
    Critics of the ``gateway theory'' point to the presence of other 
confounding factors and processes that encourage both cannabis use and 
other forms of illicit drug use. Despite these factors, the Ferguson & 
Horwood (2000) study provide a compelling set of results that support 
the hypothesis that cannabis use may encourage other forms of illicit 
drug use, including the following:

    1. Temporal sequence: There was clear evidence that the use of 
cannabis almost invariably preceded the onset of other forms of 
illicit drug use.
    2. Dose-Response: There was clear evidence of a very strong and 
consistent dose-response relationship in which increasing cannabis 
use was associated with increasing risks of the onset of illicit 
drug use.
    3. Resilience to control for confounding: Even following control 
for a range of prospectively measured social, family and individual 
factors, strong and consistent associations remained between 
cannabis use and the onset of other forms of illicit drug use. And,
    4. Specificity of associations: The association could not be 
explained as reflecting a more general process of transition to 
adolescent deviant behavior since even after control for 
contemporaneously assessed measures of juvenile offending, alcohol 
use, cigarette smoking, unemployment and related measures, strong 
and consistent relationships between cannabis use and the onset of 
other forms of illicit drugs remained.

    A suggested view of the ``gateway hypothesis'' states that the use 
of cannabis may be associated with increasing risks of other forms of 
illicit drug use, with this relationship being mediated by affiliations 
with deviant peers and other non-observed processes that may encourage 
those who use cannabis (and particularly heavy users) to experiment 
with, and use, other illicit drugs.
    While marijuana is clearly not the only gateway to the use of other 
illicit drugs it is one of the three most typical drugs in the 
adolescent's armamentarium. The increased avenues to imported and 
``home-grown'' marijuana which contain behaviorally-active doses of THC 
and CBD pose a serious threat to the health and well-being of this 
dimension of society.
    Taylor et al. (2000) evaluated the relationship between cannabis 
dependence and respiratory symptoms and lung function in young adults, 
21 years of age, while controlling for the effects of cigarette 
smoking. The researchers found significant respiratory symptoms and 
changes in spirometry occur in cannabis-dependent individuals at age 21 
years, even though the cannabis smoking history is of relatively short 
duration. The likelihood of reporting a broad range of respiratory 
symptoms was significantly increased in those who were either cannabis-
dependent or smoked tobacco or both compared to non-smokers. The 
symptoms most frequently and significantly associated with cannabis 
dependence were early morning sputum production (144% greater 
prevalence than non-smokers). Overall, respiratory symptoms in study 
members who met strict criteria for cannabis dependence were comparable 
to those of tobacco smokers consuming 1-10 cigarettes daily. In 
subjects who were both tobacco users and were cannabis-dependent, some 
effects seem to be additive, notably early morning sputum production, 
which occurred 8 times more frequently than non-smokers.
    One of the greatest concerns to society regarding \9\-THC 
is the behavioral toxicity produced by the drug. \9\-THC 
intoxication is associated with impairments in memory, motor 
coordination, cognition, judgement, motivation, sensation, perception 
and mood (cf., Jaffe, 1993). The consequences produced by \9\-
THC-induced behavioral impairments can greatly impact the individual 
and society in general. These impairments result in occupational, 
household, or airplane, train, truck, bus or automobile accidents, 
given that individuals may be attending school, working, or operating a 
motor vehicle under the influence of the drug. In the most general 
sense, impaired driving can be seen as a failure to exercise the 
expected degree of prudence or control necessary to ensure road safety. 
The operations of a motor vehicle are clearly a skilled performance 
that requires controlled and flexible use of a person's intellectual 
and perceptual resources. Cannabis interferes with resource allocations 
in both cognitive and attentional tasks.
    In 1999, Ehrenreich et al., examined the detrimental effects of 
chronic interference by cannabis with the endogenous cannabinoid 
systems during peripubertal development in humans. As an index of 
cannabinoid action, visual scanning and other attentional factors were 
examined in 99 individuals who exclusively used cannabis. Early-onset 
cannabis use (onset before the age of 16) showed significant 
impairments in attention in adulthood. These persistent attentional 
deficits may interact with the activities of daily living, such as 
operating an automobile.
    Kurzthaler et al., (1999) examined the effects of cannabis on a 
cognitive test battery and driving performance skills. The demonstrated 
significant impairments in the verbal memory and the trail making tests 
in this study reflect parallel compromises in associative control that 
is acknowledged as a cognitive process inherent in memory function 
immediately after smoking cannabis. Applied to the question of driving 
ability, the authors suggest that the missing functions would signify 
that a driver under acute cannabis influences would not be able to use 
acquired knowledge from earlier experiences adequately to ensure road 
safety.
    Recently, the National Highway Traffic Safety Administration 
(NHTSA; 1998, 1999, 2000) conducted a study with the Institute for 
Human Psychopharmacology at Maastricht University in The Netherlands. 
Low dose and high dose THC administered alone, and with alcohol were 
examined in two on-road driving situations: (1) The Road Tracking Test, 
measuring a driver's ability to maintain a constant speed of 62 mph and 
a steady lateral position between the boundaries of the right traffic 
lane; and (2) the Car Following Test, measuring a drivers' reaction 
times and ability to maintain distance between vehicles while driving 
164 ft. behind a vehicle that executed a series of alternating 
accelerations and decelerations. Both levels of THC alone, and alcohol 
alone, significantly impaired performances on BOTH road tests compared 
with baseline. Alcohol and the high dose of THC produced 36% decrements 
in reaction time; because the test vehicles were traveling at 59 mph, 
the delayed reaction times meant that the vehicle traveled, on average, 
an additional 139 feet beyond the point where the subjects began to 
decelerate. Even the lower dose of THC by itself retarded reaction 
times by 0.9 seconds. The NHTSA concluded that even in low to moderate 
doses, marijuana impairs driving performance.
    In a related analysis, Yesavage, Leirer, Denari, & Hollister (1985) 
examined the acute and delayed effects of smoking one marijuana 
cigarette containing 1.9% THC (19 mg of THC) on aircraft pilot 
performance. Ten private pilot licensed subjects were trained in a 
flight simulator prior to marijuana exposure. Flight simulator 
performance was

[[Page 20069]]

measured by the number of aileron (lateral control), elevator (vertical 
control) and throttle changes; the size of these control changes; the 
distance off the center of the runway on landing; and the average 
lateral and vertical deviation from an ideal glideslope and center line 
over the final mile of the approach. Compared to baseline performance, 
significant differences occurred in all variables at 1 and 4 hours 
after smoking, except for the numbers of throttle and elevator changes 
at 4 hours. Most importantly, at 24 hours after a single marijuana 
cigarette, there were significant impairments in the number and size of 
aileron (lateral control) changes, size of elevator changes, distance 
off-center on landing, and vertical and lateral deviations on approach 
to landing. Interestingly, despite these performance deficits, the 
pilots reported no significant subjective awareness of their 
impairments at 24 hours. It is noteworthy that a fatal crash in which a 
pilot had a positive THC screen involved similar landing misjudgments.
    In addition to causing unsafe conditions, marijuana use results in 
decreased performance and lost productivity in the workplace, including 
injuries, absenteeism, and increased health care costs. A NIDA report 
on drugs in the workplace summarized the prevalence of marijuana use in 
the workplace and its impact on society. This report found that in 
1989, one in nine working people (11%) reported current use of 
marijuana (Gust and Walsh, 1989). Recent DAWN data and other surveys 
indicate that marijuana use is increasing, especially among younger and 
working age individuals.
    Bray, Zarkin, Ringwalt, & Qi (2000) estimated the impact of age of 
dropout on the relationship between marijuana use and high school 
dropouts using four longitudinal surveys from students in the 
Southeastern U.S. public school system. Their results suggested that 
marijuana initiation was positively related to high school dropout. 
Although the magnitude and the significance of the relationship varied 
with age of dropout and the other substances used, the overall effect 
represented an odds-ratio of approximately 2.3. These data suggest that 
an individual is approximately 2.3 times more likely to drop out of 
school than an individual who has not initiated marijuana use.
    When DEA evaluates a drug for control or rescheduling, whether the 
substance creates dangers to the public health, in addition to or 
because of its abuse potential, must be considered. The risk to the 
public health of a substance may manifest itself in many ways. Abuse of 
a substance may affect the physical and/or psychological functioning of 
an individual abuser, it may have disruptive effects on the abuser's 
family, friends, work environment, and society in general. Abuse of 
certain substances leads to a number of antisocial behaviors, including 
violent behavior, endangering others, criminal activity, and driving 
while intoxicated. Data examined under this factor ranges from 
preclinical toxicity to postmarketing adverse reactions in humans. DEA 
reviews data from many sources, including forensic laboratory analyses, 
crime laboratories, medical examiners, poison control centers, 
substance abuse treatment centers, and the scientific and medical 
literature.
    In its official report titled ``Marijuana and Medicine: Assessing 
the Science Base'', the Institute of Medicine highlighted a number of 
risks to the public health as a result of cannabis consumption:

    (1) Cognitive impairments associated with acutely administered 
marijuana limit the activities that people would be able to do 
safely or productively. For example, no one under the influence of 
marijuana or THC should drive a vehicle or operate potentially 
dangerous equipment (Page 107).
    (2) The most compelling concerns regarding marijuana smoking in 
HIV/AIDS patients are the possible effects of marijuana on immunity. 
Reports of opportunistic fungal and bacterial pneumonia in AIDS 
patients who used marijuana suggest that marijuana smoking either 
suppresses the immune system or exposes patients to an added burden 
of pathogens. In summary, patients with pre-existing immune deficits 
due to AIDS should be expected to be vulnerable to serious harm 
caused by smoking marijuana. The relative contribution of marijuana 
smoke versus THC or other cannabinoids is not known. (Page 116-117)
    (3) DNA alterations are known to be early events in the 
development of cancer, and have been observed in the lymphocytes of 
pregnant marijuana smokers and in those of their newborns. This is 
an important study because the investigators were careful to exclude 
tobacco smokers; a problem in previous studies that cited mutagenic 
effects of marijuana smoke. (Page 118-119)
    (4) * * * factors influence the safety of marijuana or 
cannabinoid drugs for medical use: the delivery system, the use of 
plant material, and the side effects of cannabinoid drugs. (1) 
Smoking marijuana is clearly harmful, especially in people with 
chronic conditions, and is not an ideal drug delivery system. (2) 
Plants are of uncertain composition, which renders their effects 
equally uncertain, so they constitute an undesirable medication. 
(Page 127)

(7) Its Psychic or Physiological Dependence Liability

    The ``dopaminergic hypothesis of drug abuse'' is not the only 
explanation for the neurochemical actions of drugs. The nucleus 
accumbens/ventral striatum areas of the brain, typically referred to as 
simply the Nucleus Accumbens (NAc), represents a critical site for 
mediating the rewarding or hedonic properties of several classes of 
abused drugs, including alcohol, opioids, and psychomotor stimulants 
(Gardner & Vorel, 1998; Koob, 1992; Koob et al., 1998; Wise, 1996; Wise 
& Bozarth, 1987). It is generally appreciated that all of these drugs 
augment extracellular dopamine levels in the NAc and that this action 
contributes to their rewarding properties. However, recent evidence 
also suggests that many drugs of abuse have dopamine-independent 
interactions with Nac neuronal activity (Carlezon & Wise, 1996; Chieng 
& Williams, 1998; Koob, 1992; Martin et al., 1997; Yuan et al., 1992). 
Recent studies conducted at the Cellular Neurobiology Branch of the 
NIDA by Hoffman & Lupica (2001) concluded that THC modulates NAc 
glutamatergic functioning of dopamine. These authors suggested that 
increases in Nac dopamine levels may be a useful neurochemical index of 
drug reward but do not fully account for the complex processing of fast 
synaptic activity by this neuromodulator in the Nac. Moreover, because 
both glutamatergic and GABAergic inputs to medium spiny neurons are 
directly inhibited by dopamine, as well as by drugs of abuse. It is 
likely that these effects contribute to the abuse liability of 
marijuana.
    In addition, the petitioner's global statements about the role of 
dopamine, the reinforcing effects of marijuana and other drugs, and the 
predictive validity of animal self-administration studies with 
marijuana and abuse potential in humans are not supported by the 
scientific literature. For example:
    (1) There are drugs that do not function through dopaminergic 
systems that are self-administered by animals and humans (i.e., 
barbiturates, benzodiazepines, PCP).
    (2) There are drugs that are readily self-administered by animals 
that are not abused by man (antihistamines)
    (3) There are drugs that are abused by humans that are not readily 
self-administered by animals (hallucinogens and hallucinogenic 
phenethylamines, nicotine, caffeine).
    (4) There are drugs that have no effect on dopamine that are self-
administered

[[Page 20070]]

by animals and not abused by humans (i.e., antihistamines).

Physical Dependence in Animals

    Abrupt withdrawal from 9-THC can produce a mild 
spontaneous withdrawal syndrome in animals, including increased motor 
activity and grooming in rats, decreased seizure threshold in mice and 
increased aggressiveness, irritability and altered operant performance 
in rhesus monkeys (cf., Pertwee, 1991). The failure to observe profound 
withdrawal signs following abrupt discontinuation of 
9-THC may be due to (1) its long half-life in 
plasma and (2) slowly waning levels of 9-THC and 
its metabolites that continue to permit receptor adaptation.
    Recently the discovery of a cannabinoid receptor antagonist 
demonstrates that a profound precipitated withdrawal syndrome can be 
produced in 9-THC tolerant animals after twice 
daily injections (Tsou et al., 1995) or continuous infusion (Aceto et 
al., 1995, 1996). In rats continuously infused with low doses 
9-THC for four days, the cannabinoid antagonist 
precipitated a behavioral withdrawal syndrome, including scratching, 
face rubbing, licking, wet dog shakes, arched back and ptosis (Aceto et 
al., 1996). This chronic low dose regimen consisted of 0.5, 1, 2, 4 mg/
kg/day 9-THC on days 1 through 4; 5 and 25-fold 
higher 9-THC doses were used for the medium and 
high dose regimens, respectively. The precipitated withdrawal syndrome 
was dose-dependently more severe in the medium and high THC dose 
groups.

Physical Dependence in Humans

    Signs of withdrawal have been demonstrated after studies with 
9-THC. Although the intensity of the withdrawal 
syndrome is related to the daily dose and frequency of administration, 
in general, the signs of 9-THC withdrawal have been 
relatively mild (cf., Pertwee, 1991). This withdrawal syndrome has been 
compared to that of a short-term, low dose treatment with an opioid or 
ethanol, and includes changes in mood, sleep, heart rate body 
temperature, and appetite. Other signs such as irritability, 
restlessness, tremor mild nausea, hot flashes and sweating have also 
been noted (cf., Jones, 1983).
    A withdrawal syndrome was reported after the discontinuation of 
oral THC in volunteers receiving dronabinol dosages of 210 mg/day for 
12 to 16 consecutive days (PDR, 1997). This was 42-times the 
recommended dose of 2.5 mg, b.i.d. Within 12 hours after 
discontinuation, these volunteers manifested withdrawal symptoms such 
as irritability, insomnia, and restlessness. By approximately 24 hours 
after THC discontinuation, there was an intensification of withdrawal 
symptoms to include ``hot flashes'', sweating, rhinorrhea, loose 
stools, hiccoughs, and anorexia. These withdrawal symptoms gradually 
dissipated over the next 48 hours. EEG changes consistent with the 
effects of drug withdrawal (hyperexcitation) were recorded in patients 
after abrupt challenge. Patients also complained of disturbed sleep for 
several weeks after discontinuation of high doses of dronabinol. The 
intensity of the cannabinoid withdrawal syndrome is related by the 
chronic dose and by the frequency of chronic administration. There is 
also evidence that the cannabinoid withdrawal symptoms can be reversed 
by the administration of marijuana and 9-THC, or by 
treatment with a barbiturate (hexobarbital) or ethanol (Pertwee, 1991).
    An acute withdrawal syndrome or ``hangover'' has been reported by 
Chait, Fischman, & Schuster (1985) developing approximately 9 hours 
after smoking a 1 g marijuana cigarette containing 2.9% THC. Five of 
twelve subjects reported themselves as ``dopey and hung over'' the 
morning after smoking the single cigarette. In a 10 second and 30 
second time-production task significant marijuana hangover effects were 
found. The effect on the time production task is of interest since the 
effect obtained the morning after smoking marijuana was opposite to 
that observed acutely after smoking marijuana. These data may suggest 
an opponent compensatory rebound which may underlie the development of 
tolerance over periods of chronic marijuana exposure. Scores on the 
benzedrine-group (BG) scale, a stimulant scale of the Addiction 
Research Center Inventory (ARCI) consisting mainly of terms relating to 
intellectual efficiency and energy, were significantly higher the 
morning after marijuana smoking, as well. Chait, Fischman, & Schuster 
also reported increases on the amphetamine (A) scale of the ARCI, a 
measure of the dose-related effects of d-amphetamine. Cousens & 
DiMascio (1973) have previously reported a similar ``hangover'' and 
``speed of thought alterations'' in subjects the morning after they had 
received a 30 mg oral dose of 9-THC. Like the 
``hangover'' associated with high dose ethyl alcohol consumption, the 
hangover from marijuana may be qualitatively identical to, and differ 
only on an intensity dimension from, the withdrawal syndrome produced 
from chronic consumption (cf. Gauvin, Cheng, Holloway, 1993).
    As described above, Haney et al. have recently described abstinence 
symptoms of an acute withdrawal syndrome following high (30 mg q.i.d.) 
and low (20 mg q.i.d) dose administrations of oral THC (Haney et al., 
1999a) and following 5 puffs of high (3.1%) and low (1.8%) THC-
containing smoked marijuana cigarettes (Haney et al., 1999b). Both of 
these studies have delineated a withdrawal syndrome from concentrations 
of THC significantly lower than those reported in any other previous 
study and, for the first time, clearly identified a marijuana 
withdrawal syndrome detected at low levels of THC exposure that do not 
produce tolerance. These data suggest that dependence on THC may in 
fact be an important consequence of repeated, daily exposure to 
cannabinoids and that daily marijuana use may be maintained, at least 
in part, by the alleviation of abstinence symptoms.
    As stated above, Budney, Novy, & Hughes (1999) have recently 
examined the withdrawal symptomology in chronic marijuana users seeking 
treatment for their dependence. The majority of the subjects (85%) 
reported that they had experienced symptoms of at least moderate 
severity and 47% experienced greater than four symptoms rated as 
severe. The most reported mood symptoms associated with the withdrawal 
state were irritability, nervousness, depression, and anger. Some of 
the behavioral characteristics of the marijuana withdrawal syndrome 
were craving, restlessness, sleep disruptions, strange dreams, changes 
in appetite, and violent outbursts. These data clearly support the 
validity and clinical significance of a marijuana withdrawal syndrome 
in man. Large-scale population studies have also reported significant 
rates of cannabis dependence (Kessler et al., 1994; Farrell et al., 
1998), particularly in prison and homeless populations. Similar reports 
of cannabis dependence in withdrawal in other populations have been 
previously discussed (above; Crowley et al. (1998); Kouri & Pope 
(2000)).

Psychological Dependence in Humans

    In addition to the physical dependence produced by abrupt 
withdrawal from 9-THC, psychological dependence on 
9-THC can also be demonstrated. Case reports and 
clinical studies show that frequency of 9-THC use 
(most often as marijuana) escalates over time, there is evidence that 
individuals increase the number, doses, and potency of marijuana 
cigarettes. Data have clearly shown that tolerance

[[Page 20071]]

to the stimulus effects of the drug develops which could lead to drug 
seeking behavior (Pertwee, 1991; Aceto et al., 1996; Kelly et al., 
1993, 1994; Balster and Prescott, 1992; Mendelson et al., 1976; 
Mendelson and Mello, 1985; Mello, 1989). Several studies have reported 
that patterns of marijuana smoking and increased quantity of marijuana 
smoked were related to social context and drug availability (Kelly et 
al., 1994; Mendelson and Mello, 1985; Mello, 1989). There have been, 
however, other studies which have demonstrated that the magnitude of 
many of the behavioral effects produced by 9-THC 
and other synthetic cannabinoids lessens with repeated exposure while 
also demonstrating that tolerance did not develop to the euphorigenic 
activity, or the ``high'' from smoked marijuana (Dewey, 1986; Perez-
Reyes et al., 1991). Recent electrophysiological data from animals 
suggests that the response of VTA dopamine neurons do not diminish 
during repeated exposure to cannabinoids, and that this may underlie 
the lack of tolerance to the euphoric effects of marijuana even with 
chronic use (Wu & French, 2000).
    The problems of psychological dependence associated with marijuana 
(THC) abuse are apparent from DAWN reports and survey data from the 
National Household Survey on Drug Abuse and the Monitoring the Future 
study. These databases show that the incidence of chronic daily 
marijuana use and adverse events associated with its use are 
increasing, especially among the young. At the same time, perception of 
risk has decreased and availability is widespread (cf., NIDA, 1996). 
These factors contribute to perpetuating the continued use of the 
marijuana.
(8) Whether The Substance Is an Immediate Precursor of a Substance 
Already Controlled Under This Subchapter.
    According to the legal definition, marijuana (Cannabis sativa L.) 
is not an immediate precursor of a scheduled controlled substance. 
However, cannabidiol is a precursor for delta-9-tetrahydrocannabinol, a 
Schedule I substance under the CSA.

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