[Federal Register Volume 66, Number 75 (Wednesday, April 18, 2001)]
[Notices]
[Pages 20038-20076]
From the Federal Register Online via the Government Publishing 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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