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
- 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.
- Evaluating Marijuana Under the Eight Factors
This section presents scientific and medical knowledge about
marijuana under the eight required factors.
[[Page 20040]]
- 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:
- 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.
- There is a significant diversion of the drug or substance from
legitimate drug channels.
- 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 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.
- 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
[[Page 20041]]
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.
- 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).
- 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.
- 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).
- 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-
[[Page 20043]]
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).
- 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
- 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
- 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.
- 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.
- 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).
- 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.
- 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.
- 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]]
- 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.
- 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.
- 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:
- 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.
- 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:
- The drug’s chemistry is known and reproducible;
- There are adequate safety studies;
- There are adequate and well-controlled studies proving efficacy;
- The drug is accepted by qualified experts; and
- 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.”
- 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.
References
Adams, I.B., and Martin, B.R. Cannabis: Pharmacology and toxicology
in animals and humans. Addiction 1996, 91(11):1585-1614.
Agurell, S., Dewey, W.L., and Willett, R.E., eds. The Cannabinoids:
Chemical, Pharmacologic, and Therapeutic Aspects. New York: Academic
Press, 1984.
Agurell, S.; Halldin, M.; Lindgren, J.E.; Ohlsson, A.; Widman, M.;
Gillespie, H.; and Hollister, L. Pharmacokinetics and metabolism of
delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on
man. Pharmacol Rev. 1986, 38(1), 21-43.
Ameri, A. The effects of cannabinoids on the brain. Progress in
Neurobiology 1999, 58(4), 315-348.
Balster, R.L., Prescott, W.R.,) \9\-Tetrahydrocannabinol
discrimination in rats as a model for cannabis intoxication.
Neurosci. & Biobehav. Rev. 1992, 16(1), 55-62.
Barnett, G.; Licko, V.; and Thompson, T. Behavioral pharmacokinetics
of marijuana. Psychopharmacology 1985, 85(1), 51-56.
Budney AJ, Novy PL, Hughes JR. Marijuana withdrawal among adults
seeking treatment for marijuana dependence. Addiction 1999,
94(9):1311-22 Community Epidemiology Work Group, National Institutes
of Health, National Institute on Drug Abuse, Epidemiologic Trends in
Drug Abuse, Volume I: Highlights and Executive Summary, June 2000,
http://www.nida.nih.gov/CEWG/pubs.html
Department of Health and Human Services. Announcement of the
Department of Health and Human Services Guidance on Procedures for
the Provision of Marijuana for Medical Research. May 21, 1999.
(http://grants.nih.gov/grants/guide/notice-files/not99-091.html).
Drug Abuse Warning Network. Year-End 1999 Emergency Department Data
from the Drug Abuse Warning Network. Department of Health and Human
Services. Substance Abuse and Mental Health Services Administration.
National Clearinghouse for Alcohol and Drug information. Rockville,
MD.
Drug Abuse Warning Network. Annual Medical Examiner Data 1998.
Department of Health and Human Services. Substance Abuse and Mental
Health Services Administration. National Clearinghouse for Alcohol
and Drug information. Rockville, MD.
DSM-IV-TR 2000: Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision 4th Edition–Text Revision
American Psychiatric Association, Publisher: American Psychiatric
Press, Incorporated, Pub. Date: July 2000, Edition Desc: 4th
Edition–Text Revision.
Dewey, W. L., Martin, B. R., May, E. L. Cannabinoid stereoisomers:
pharmacological effects. In Smith, D. F. (Ed.) CRC Handbook of
stereoisomers: drugs in psychopharmacology, 317-326 (Boca Raton, FL,
CRC Press), 1984.
Fried, P. A., Watkinson, B. 36- and 48-month neurobehabioral follow-
up of children prenatally exposed to marijuana, cigarettes and
alcohol. J. Dev. Behav. Pediatr. 1987, 8, 318-326.
Fried, P. A., Watkinson, B., Gray, R. A follow-up study of
attentional behavior in 6-year-old children exposed prenatally to
marihuana, cigarettes and alcohol. Neurotoxicol. Teratol. 1992, 14,
299-311.
Fried, P. A., Watkinson, B., Gray, R. Differential effects on
cognitive functioning in 9- to 12-year olds prenatally exposed to
cigarettes and marihuana. Neurotoxicol. Teratol. 1998, 20(3), 293-
306.
French, E.D. Delta\9\-Tetrahydrocannabinol excites rat VTA dopamine
neurons through activation of cannabinoid CB1 but not opioid
receptors. Neurosci Lett 1997, 226, 159-162.
Fung, M., Gallagher, C., Machtay, M. Lung and aeo-digestive cancers
in young marijuana smokers. Tumori 1999, 85 (2), 140-142.
Galiegui, S.; Mary, S.; Marchand, J.; Dussossoy, D.; Carriere, D.;
Carayon, P.; Bouaboula, M; Shire, D.; Le Fur, g.; Casellas, P.
Expression of central and peripheral cannabinoid receptors in human
immune tissues and leukocyte subpopulations. Eur J Biochem. 1995,
232(1), 54-61.
Gaoni, Y., Mechoulam, R. Isolation, structure, and partial synthesis
of an active constituent of hashish. J. Am. Chem. Soc. 1964, 86,
1646-1947.
Gerard, C. M., Mollereau, C., Vassart, G., Parmentier, M. Molecular
cloning of a human cannabinoid receptor which is also expressed in
testis. : Biochem J. 1991, 279, 129-34.
Gessa, G.L., Melis, M., Munoni, A.L., Diana, M. Cannabinoids
activate mesolimbic dopamine neurons by an action on cannabinoid CB1
receptors. Eur J Pharmacol 1998, 341(1), 39-44.
Graham, J.D.P., ed. Cannabis and Health. New York: Academic Press,
1976.
Griffith, D. R., Azuma, S. D., Chasnoff, I. J. Three-year outcome of
children exposed prenatally to drugs. J. Am. Acad. Child Adolesc.
Psychiatry 1994, 33, 20-27.
Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. Abstinence
symptoms following smoked marijuana in humans. Psychopharmacology
(Berl) 1999, 141(4):395-404.
Hanus, L., Breuer, A., Tchilibon, S., Shiloah, S., Goldenberg, D.,
Horowitz, M., Pertwee, R.G., Roos, R. A., Mechoulam, R., Fride, E.
HU-308: a specific agonist for CB(2), a peripheral Cannabinoid
receptor. Proc. Natl. Acad. Sci. USA 1999, 96, 14228-33.
Harvey, D.J., ed. Satellite Symposium on Cannabis (3rd: 1984:
Oxford, England) Marihuana ’84: Proceedings of the Oxford Symposium
on Cannabis. Washington, DC: IRL Press, 1985.
Herkenham, M. Cannabinoid receptor localization in brain:
Relationship to motor and reward systems. In: Kalivas, P.W., and
Samson, H.H., eds. The neurobiology of drug and alcohol addiction.
Ann N Y Acad Sci 1992, 654, 19-32.
Herkenham, M., Lynn, A.B., Little, M.D., Johnson, M.R., Melvin,
L.S., de Costa, B.R., Rice, K.C. Cannabinoid receptor localization
in Brain. Proc. Natl. Acad. Sci. USA. 1990, 87, 1932-1936.
Herning, R.I.; Hooker, W.D.; and Jones, R.T. Tetrahydrocannabinol
content and differences in marijuana smoking behavior.
Psychopharmacology 1986, 90(2):160-162.
Hively, R.L., Mosher, W.A., Hoffman, F.W. Isolation of trans-)9-
tetrahydrocannabinol from marihuana. J. Am. Chem. Soc. 1966, 88,
1832-1833.
Hollister, L.E. Health aspects of cannabis. Pharmacological Rev.
1986, 38, 1-20.
Hollister, L.E. Cannabis. (Literature review). Acta Psychiatr Scand
(Suppl) 1988, 78, 108-118.
Huestis, M.A., Sampson, A.H., Holicky, B.J., Henningfield, J.E.,
Cone, E.J. Characterization of the absorption phase of marijuana
smoking. Clin. Pharmacol. Ther. 1992a, 52, 31-41.
Huestis, M.A.; Henningfield, J.E.; and Cone,
[[Page 20053]]
E.J. Blood Cannabinoids. 1. Absorption of THC and formation of 11-
OH-THC and THC COOH during and after smoking marijuana. J Anal
Toxicol 1992b, 16(5), 276-282.
Johansson, E.; Halldin, M.M.; Agurell, S.; Hollister, L.E.; and
Gillespie, H.K. Terminal elimination plasma half-life of delta 1-
tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana. Eur
J Clin Pharmacol 1989, 37(3), 273-277.
Jones, R.T.; Benowitz, N.L.; and Herning, R.I. Clinical relevance of
cannabis tolerance and dependence. J Clin Pharmacol 1981, 21,143S-
152S.
Koob, G.F. Neural mechanisms of drug reinforcement. Ann. N Y Acad
Sci 1992, 654, 171-191.
Lane JD, Phillips-Bute BG. Caffeine deprivation affects vigilance
performance and mood. Physiol Behav 1998 65, 171-5.
Lemberger L., Rubin A. The physiologic disposition of marihuana in
man, Life Sci. 1975,17, 1637-42.
Lemberger L., Silberstein, S.D., Axelrod, J., Kopin, I.J. Marihuana:
studies on the disposition and metabolism of delta-9-
tetrahydrocannabinol in man. Science 1970, 170, 1320-1322.
Lemberger L., Weiss, J.L., Watanabe, A.M., Galanter, I.M., Wyatt,
R.J., Cardon, P. V. Delta-9-tetrahydrocannabinol: temporal
correlation of the psychological effects and blood levels after
various routes of administration. New Eng. J. Med. 1972a, 286(13),
685-688.
Lemberger, L., Crabtree, R.E., Rowe, H.M. 11-Hydroxy-)9-
tetrahydrocannabinol: pharmacology, disposition and metabolism of a
major metabolite of marihuana in man. Science 1972b, 177, 62-63.
Martin, B.R.; Mechoulam, R., Razdan, R.K. Discovery and
characterization of endogenous cannabinoids. Life Sci. 1999, 65,
573-595.
Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner,
T.I. Structure of a cannabinoid receptor and functional expression
of the cloned cDNA. Nature 1990, 346, 561-564.
Mechoulam, R. Cannabinoid chemistry. In Mechoulam, R. (ED.)
Marijuana, pp.2-88 (New York, NY, Academic Press, Inc.), 1973.
Monitoring the Future. National Results on Adolescent Drug Use.
Overview of 1999 Key findings, 1999. Department of Health and Human
services. National Institute on Drug Abuse. Rockville, MD. (http://
monitoringthefuture.org)
National Institutes of Health (NIH). Workshop on the medical Utility
of Marijuana, February 19-20, 1997. (www.nih.gov/news/medmarijuana/
MedicalMarijuana.htm)
NHSDA. Summary of Findings from the 1999 National Household Survey
on Drug Abuse. Office of Applied Studies. Department of Health and
Human services. Substance Abuse and Mental Health Services
Administration. National Clearinghouse for Alcohol and Drug
information. Rockville, MD.
Office of National Drug Control Policy. The National Drug Control
Strategy: 2000 Annual Report. Superintendent of Documents, Mail
Stop: SSOP, Washington, DC.
Oviedo, A., Glowa, J., Herkenham, M. Chronic cannabinoid
administration alters cannabinoid receptor binding in rat brain: a
quantitative autoradiographic study. Brain Res. 1993, 616, 293-302.
Rinaldi-Carmona, M., Barth F., Heaulme, M., Shire, D., Calandra, B.,
Congy, C., Martinez, S., Maruani, J., Neliat, G., Caput, D., et al.
SR141716A, a potent and selective antagonist of the brain
cannabinoid receptor. FEBS Letters 1994, 350, 240-244.
Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy
C, Oustric D, Sarran M, Bouaboula M, Calandra B, Portier M, Shire D,
Breliere JC, Le Fur GL, SR 144528, the first potent and selective
antagonist of the CB2 cannabinoid receptor. J Pharmacol
Exp Ther. 1998 , 284(2), 644-50.
Rodriguez de Fonseca F, Gorriti, M.A., Fernandez-Ruiz, J.J., Palomo,
T., Ramos, J.A. Downregulation of rat brain cannabinoid binding
sites after chronic delta 9-tetrahydrocannabinoil treatment.
Phamacol. Biochem. Behav. 1994, 47 (1), 33-40.
Ross, S.A. and ElSohlyy, M.A. Constituents of Cannabis Sativa L.
XXVIII. A review of the natural constituents:1980-1994. Zagazig J.
Pharm. Sci. 1995, 4 (2), 1-10.
Sanudo-Pena M.C., Tsou, K., Delay, E.R., Hohman, A.G., Force, M.,
Walker, J.M. Endogenous cannabinoids as an aversive or counter-
rewarding system in the rat. Neurosci. Lett., 223, 125-128, 1997.
Treatment Episode Data Set (TEDS): 1993-1998. National Admissions to
Substance Abuse Treatment Services. Department of Health and Human
services. Substance Abuse and Mental Health Services Administration.
National Clearinghouse for Alcohol and Drug information. Rockville,
MD.
Wesson, D.R.; Washburn, P. Current patterns of drug abuse that
involve smoking. In Research Findings on Smoking of Abused
Substances, Chiang, C.N.; Hawks, R.L. (ED.) NIDA Research Monograph,
99:5-11, 1990.