HHS Review of the 1995 Marijuana Rescheduling Petition Federal Register: April 18, 2001 (Volume 66, Number 75) Pages 20040 – 20054

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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.


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


      Sincerely yours,

David Satcher,

Assistant Secretary for Health and Surgeon General.


Basis for the Recommendation for Maintaining Marijuana in Schedule

I of the Controlled Substances Act

  1. 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


    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.

  1. Evaluating Marijuana Under the Eight Factors

    This section presents scientific and medical knowledge about

marijuana under the eight required factors.

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  1. Its Actual or Relative Potential for Abuse

    The CSA defines marijuana as the following:

    All parts of the plant Cannabis Sativa L., whether growing or

not; the seeds thereof; the resin extracted from any part of such

plant; and every compound, manufacture, salt, derivative, mixture,

or preparation of such plant, its seeds or resin. Such term does not

include the mature stalks of such plant, fiber produced from such

stalks, oil or cake made from the seeds of such plant, any other

compound, manufacture, salt, derivative, mixture, or preparation of

such mature stalks (except the resin extracted therefrom), fiber,

oil, or cake, or the sterilized seed of such plant which is

incapable of germination.

21 U.S.C. 802(16).

    The term “abuse” is not defined in the CSA. However, the

legislative history of the CSA suggests the following in determining

whether a particular drug or substance has a potential for abuse:

  1. 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.

  1. There is a significant diversion of the drug or substance from

legitimate drug channels.

  1. 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.

  1. 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,


    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


    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


  1. There is evidence that individuals are taking the substance in

amounts sufficient to create a hazard to their health or to the safety

of other individuals or to the community.

    Marijuana is a widely used substance. The pharmacology of the

psychoactive constituents of marijuana (including delta\9\-THC, the

primary psychoactive ingredient in marijuana) has been studied

extensively in animals and humans and is discussed in more detail below

in Section 2, “Scientific Evidence of its Pharmacological Effects, if

Known.” Although it is difficult to determine the full extent of

marijuana abuse, extensive data from the National Institute on Drug

Abuse (NIDA) and from the Substance Abuse Mental Health Services

Administration (SAMHSA) are available. These data are discussed in

detail in Section 4 “Its History and Current Pattern of Abuse;”

Section 5, “The Scope, Duration, and Significance of Abuse;” and

Section 6, “What, if any Risk There is to the Public Health.”

    According to the National Household Survey on Drug Abuse (NHSDA),

of the 14.8 million Americans who used illicit drugs on a monthly basis

in 1999, 11.2 million used marijuana. In 1998, 1.6 million children

between the ages of 12 and 17 used marijuana for the first time. (See

the discussion of the 1999 NHSDA in Section 4). A 1999 survey of 8th,

10th, and 12th grade students indicates that marijuana is the most

widely used illicit drug in this age group. By 12th grade, 37.8% of

students report having used marijuana in the past year, and 23.1%

report using it monthly. (See the

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discussion of the Monitoring the Future Study in Section 4). Primary

marijuana abuse accounts for 13% of the admissions to treatment

facilities for substance abuse, with 92% of those admitted having used

marijuana for the first time by age 18. (See discussion of the

Treatment Episode Data Set in Section 4).

    The Drug Abuse Warning Network (DAWN) is a national probability

survey of hospitals with emergency departments (EDs). DAWN is designed

to obtain information on ED episodes that are induced by or related to

the use of an illegal drug or the non-medical use of a legal drug. DAWN

recently reported 87,150 ED drug mentions for marijuana/ hashish in

1999, representing 16 % of all drug-related episodes in 1999. (See

discussion of DAWN in Section 4). In 1999, DAWN data show that out of

664 medical examiner marijuana-related episodes, there were 187 deaths

in persons who had used marijuana alone. While marijuana has a low

level of toxicity when compared to other drugs of abuse, there are a

number of risks resulting from both acute and chronic use of marijuana.

These risks are discussed in full in sections 2 and 6 below.

  1. 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).

  1. 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.

  1.    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).

  1. 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,

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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


    (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


    (8) Impaired judgement, reduced co-ordination and ataxia, which can

impede driving ability or lead to an increase in risk-taking behavior

    (9) Emotional lability, incongruity of affect, dysphoria,

disorganized thinking, inability to converse logically, agitation,

paranoia, confusion, restlessness, anxiety, drowsiness and panic

attacks may occur, especially in inexperienced users or in those who

have taken a large dose

    (10) Increased appetite and short-term memory impairment are common

    Humans demonstrate a preference for higher doses of marijuana

(1.95% delta9-THC) over lower doses (0.63%

delta9-THC) (Chaitand Burke, 1994), similar to the dose

preference exhibited for many other drugs of abuse.

Animal Behavioral Effects

     Predictors of Reinforcing Effects (Self-Administration and

Conditioned Place Preference)

    One indicator of whether a drug will be reinforcing in humans is

the self-administration test in animals. Self-

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administration of marijuana, LSD, sigma receptor agonists, or

cholinergic antagonists is difficult to demonstrate in animals.

However, when it is known that humans voluntarily consume a particular

drug for its pleasurable effects, the inability to establish self-

administration with that drug in animals has no practical importance.

This is because the animal test is only useful as a rough predictor of

human behavioral response in the absence of naturalistic data. Thus,

the petitioner is incorrect that the accepted legal convention for

abuse potential is self-administration in animals and that because

marijuana does not induce self-administration in animals, it has a

lower abuse potential than drugs that easily induce self-administration

in animals. Similarly, the petitioner is incorrect that the difficulty

in inducing self-administration of marijuana in animals is due to a

lack of effect on dopamine receptors. In fact, dopamine release can be

stimulated indirectly by marijuana, following direct action of the drug

on cannabinoid receptors. However, it is important to note that while

self-administration in animals has been correlated with dopamine

function, both pleasurable and painful stimuli can evoke dopaminergic

responses. Dopamine functioning does not determine scheduling under the


    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


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.

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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


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


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


[[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).

  1. The State of Current Scientific Knowledge Regarding the Drug or

Other Substance

    This section discusses the chemistry, human pharmacokinetics, and

medical uses of marijuana.


    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


[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


    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

  1. 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

  1. 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.,


    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


[[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.

  1. 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




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




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.

  1. 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).

  1. 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


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


    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.

  1. 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.

  1. 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


    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]]

  1. 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.

  1. Whether the Substance is an Immediate Precursor of a Substance

Already Controlled Under This Article

    Marijuana is not an immediate precursor of another controlled


  1. Findings and Recommendation

    After considering the scientific and medical evidence presented

under the eight factors above, FDA finds that marijuana meets the three

criteria for placing a substance in Schedule I of the CSA under 21

U.S.C. 812(b)(1). Specifically:

  1. Marijuana Has a High Potential for Abuse

    11.2 million Americans used marijuana monthly in 1999 and 1998 data

indicate that 6.8 million Americans used marijuana weekly. A 1999 study

indicates that by 12th grade, 37.8% of students report having used

marijuana in the past year, and 23.1 % report using it monthly. In

1999, 87,150 emergency department episodes were induced by or related

to the use of marijuana/hashish, representing 16% of all drug-related

episodes. The primary motive for drug intake in 34.2 % of those

episodes was reported to be dependence. DAWN data from that same year

show that out of 664 medical examiner episodes involving marijuana,

marijuana was the only drug reported in 187 deaths. In recent years,

the proportion of primary marijuana abusers entering drug abuse

treatment programs has been increasing in major U.S. cities, ranging

from 19% in New York City to 41% in St. Louis and Denver.

    Data show that humans prefer higher doses of marijuana to lower

doses, demonstrating that marijuana has dose-dependent reinforcing

effects. Marijuana has relatively low levels of toxicity and physical

dependence as compared to other illicit drugs. However, as discussed

above, physical dependence and toxicity are not the only factors to

consider in determining a substance’s abuse potential. The large number

of individuals using marijuana on a regular basis and the vast amount

of marijuana that is available for illicit use are indicative of

widespread use. In addition, there is evidence that marijuana use can

result in psychological dependence in a certain proportion of the


  1. 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:

  1. The drug’s chemistry is known and reproducible;
  2. There are adequate safety studies;
  3. There are adequate and well-controlled studies proving efficacy;
  4. The drug is accepted by qualified experts; and
  5. 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.”

  1. There Is a Lack of Accepted Safety for Use of Marijuana Under

Medical Supervision

    There are no FDA-approved marijuana products. Marijuana does not

have a currently accepted medical use in treatment in the United States

or a currently accepted medical use with severe restrictions. As

discussed earlier, the known risks of marijuana use are not outweighed

by any potential benefits. In addition, the agency cannot conclude that

marijuana has an acceptable level of safety without assurance of a

consistent and predictable potency and without proof that the substance

is free of contamination. If marijuana is to be investigated more

widely for medical use, information and data regarding the chemistry,

manufacturing and specifications of marijuana must be developed.

Therefore, FDA concludes that, even under medical supervision,

marijuana has not been shown to have an acceptable level of safety.

    FDA therefore recommends that marijuana be maintained in Schedule I

of the CSA.

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