DEA Denial of the 1995 Marijuana Rescheduling Petition

Federal Register: April 18, 2001 (Volume 66, Number 75)

Additional Scientific Data Considered by the Drug Enforcement

Administration in Evaluating Jon Gettman’s Petition To Initiate

Rulemaking Proceedings To Reschedule Marijuana

Drug and Chemical Evaluation Section, Office of Diversion Control, Drug

Enforcement Administration, March 2001

Introduction

    On July 10, 1995, Jon Gettman petitioned the Drug Enforcement

Administration (DEA) to initiate rulemaking proceedings to reschedule

marijuana. Marijuana is currently listed in schedule I of the

Controlled Substances Act (CSA).

    Mr. Gettman proposed that DEA promulgate a rule stating that

“there is no scientific evidence that [marijuana has] sufficient abuse

potential to warrant schedule I or II status under the [CSA].”

    In accordance with the CSA, DEA gathered the necessary data and, on

December 17, 1997, forwarded that information along with Mr. Gettman’s

petition to the Department of Health and Human Services (HHS) for a

scientific and medical evaluation and scheduling recommendation. On

January 17, 2001, HHS forwarded to DEA its scientific and medical

evaluation and scheduling recommendation. The CSA requires DEA to

determine whether the HHS scientific and medical evaluation and

scheduling recommendation and “all other relevant data” constitute

substantial evidence that the drug should be rescheduled as proposed in

the petition. 21 U.S.C. 811(b). This document contains an explanation

of the “other relevant data” that DEA considered.

    In deciding whether to grant a petition to initiate rulemaking

proceedings, DEA must consider eight factors specified in 21 U.S.C.

811(c). The information contained in this document is organized

according to these eight factors.

(1) Its Actual or Relative Potential for Abuse

    Evaluation of the abuse potential of a drug is obtained, in part,

from studies in the scientific and medical literature. There are many

preclinical indicators of a drug’s behavioral and psychological effects

that, when taken together, provide an accurate prediction of the human

abuse liability. Specifically, these include assessments of the

discriminative stimulus effects, reinforcing effects, conditioned

stimulus effect, effects on operant response rates, locomotor activity,

effects on food intake and other behaviors, and the development of

tolerance and dependence (cf., Brady et al., 1990; Preston et al.,

1997). Clinical studies of the subjective and reinforcing effects in

substance abusers, interviews with substance abusers, clinical

interviews with medical professionals, and epidemiological studies

provide quantitative data on abuse liability in humans and some

indication of actual abuse trends (cf., deWit and Griffiths, 1991).

    Evidence of actual abuse and patterns of abuse are obtained from a

number of substance abuse databases, and reports of diversion and

trafficking. Specifically, data from Drug Abuse Warning Network (DAWN),

Poison

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Control Centers, System To Retrieve Investigational Drug Evidence

(STRIDE), seizures and declarations from U.S. Customs, DEA Drug Theft

Reports and other diversion and trafficking data bases are indicators

of the pattern, scope, duration and significance of abuse.

Reinforcing Effects in Animals

    As described by the petitioner, the preponderance of preclinical

studies using animal models had, to recently, shown that \9\-

THC had minimal activity in behavioral paradigms predictive of

reinforcing efficacy (i.e., self-administration paradigms; Harris et

al., 1974; Pickens et al., 1973; Deneau and Kaymakcalan, 1971). In

general, \9\-THC had been shown to be relatively ineffective

in maintaining self-administration behavior by either the intravenous

or oral routes (Kaymakcalan, 1973; Harris et al., 1974; Carney et al.,

1977; Mansbach et al., 1994). Under limited experimental parameters,

\9\-THC self-administration was demonstrated after animals

were either first trained to self-administer PCP, after a chronic

cannabinoid history was established or when maintained at 80% reduced

body weight (Pickens et al., 1973; Deneau and Kaymakcalan, 1971;

Takahashi and Singer, 1979). However, Tanda, Munzar and Goldberg of the

Intramural Preclinical Pharmacology Section of the NIDA (2000) have

clearly demonstrated that THC can act as a strong reinforcer of drug-

taking behavior in an experimental animal model, the squirrel monkey,

as it does in humans. The self-administration behavior was comparable

in intensity to that maintained by cocaine under identical conditions

and was obtained using a range of doses similar to those self-

administered by humans smoking a single marijuana cigarette.

    Although the neuropharmacological actions of \9\-THC

suggest a powerful brain substrate underlying its rewarding and

euphorigenic effects, behavioral studies of \9\-THC’s

rewarding effects had been inconclusive. Several reasons for the

previous inability by a number of laboratories to demonstrate self-

administration of \9\-THC in animals may be its relatively

slow-onset, its long-lasting behavioral effects and its insolubility in

physiological saline or water for injection (Mansbach et al., 1994).

Similar findings have been found in the animal literature with

nicotine–an avid reinforcer in humans. The strength of THC, like

nicotine, as a reinforcer in animals may be more dependent on

supplementary strengthening by ancillary stimuli than is the case for

other drugs (cf. Henningfield, 1984).

    In other behavioral and pharmacological tests used to assess

reinforcing efficacy, \9\-THC produced significant effects.

Specifically, \9\-THC augments responding for intracranial

self-stimulation by decreasing the reinforcing threshold for brain

stimulation reward. It also dose-dependently enhances dopamine efflux

in forebrain nuclei associated with reward and this enhanced efflux

occurs locally in the terminal fields within brain reward pathways

(Gardner and Lowinson, 1991; Gardner, 1992; Chen et al., 1993, 1994).

In conditioned place preference procedures, \9\-THC (2.0 and

4.0 mg/kg, i.p.) produced significant dose-dependent increases in

preference for the drug paired chamber, the magnitude of which was

similar to that seen with 5.0 mg/kg cocaine and 4.0 mg/kg morphine

(Leprore et al., 1995). However, \9\-THC also produced a

conditioned place aversion and conditioned taste aversion (Leprore et

al., 1995; Parker and Gillies, 1995). The development of taste

aversions with drug administrations that also produce place preferences

have been described as somewhat of a “drug paradox” by Goudie;

however, this has been found to occur within the “therapeutic window”

of all known drugs of abuse (cf Goudie, 1987). Goudie has concluded

that drugs can possess both reinforcing and aversive properties at the

same doses. This fact may underlie the reciprocal relationship between

the behavioral effects of THC, CBD, and THC+CBD combinations, discussed

below.

Drug Discrimination in Animals

    Preclinical drug discrimination studies with \9\-THC are

predictive of the subjective effects of cannabinoid drugs in humans and

serve as animal models of marijuana and THC intoxication in humans

(Balster and Prescott, 1992; Wiley et al., 1993b, 1995). In a variety

of species it has been found that \9\-THC shares

discriminative stimulus effects with cannabinoids that bind to CNS

cannabinoid receptors with high affinity (Compton et al., 1993; Jarbe

et al., 1989; Gold et al., 1992; Wiley et al., 1993b, 1995b; Jarbe and

Mathis, 1992) and that are psychoactive in humans (Balster and

Prescott, 1992). Furthermore, recent studies show that the

discriminative stimulus effects of \9\-THC are mediated via

the CB1 receptor subtype (Perio et al., 1996).

    Chronic \9\-THC administration to rats produced tolerance

to the discriminative stimulus effects of \9\-THC, but not to

its response rate disruptions. Specifically, tolerance to the stimulus

effects of \9\-THC increased 40-fold when supplemental doses

of up to 120 mg/kg/day \9\-THC were administered under

conditions of suspended training (Wiley et al., 1993a).

    The discriminative stimulus effects of \9\-THC appear to

be pharmacologically specific as non-cannabinoid drugs typically do not

elicit cannabimimetic effects in drug discrimination studies (Browne

and Weissman, 1981; Balster and Prescott, 1992, Gold et al., 1992;

Barrett et al., 1995; Wiley et al., 1995a). Furthermore, these studies

show that high doses of \9\-THC produce marked response rate

disruption, immobility, ataxia, sedation and ptosis in rhesus monkeys

and rats (Wiley et al., 1993b; Gold et al., 1992; Martin et al., 1995).

Clinical Abuse Potential

    Both marijuana and THC can serve as positive reinforcers in humans.

Marijuana and \9\-THC produced profiles of behavioral and

subjective effects that were similar regardless of whether the

marijuana was smoked or taken orally, as marijuana in brownies, or

orally as THC-containing capsules, although the time course of effects

differed substantially. There is a large clinical literature

documenting the subjective, reinforcing, discriminative stimulus, and

physiological effects of marijuana and THC and relating these effects

to the abuse potential of marijuana and THC (e.g., Chait et al., 1988;

Lukas et al., 1995; Kamien et al., 1994; Chait and Burke, 1994; Chait

and Pierri, 1992; Foltin et al., 1990; Azorlosa et al., 1992; Kelly et

al., 1993, 1994; Chait and Zacny, 1992; Cone et al., 1988; Mendelson

and Mello, 1984).

    These listed studies represent a fraction of the studies performed

to evaluate the abuse potential of marijuana and THC. In general, these

studies demonstrate that marijuana and THC dose-dependently increases

heart rate and ratings of “high” and “drug liking”, and alters

behavioral performance measures (e.g., Azorlosa et al., 1992; Kelly et

al., 1993, 1994; Chait and Zacny, 1992; Kamien et al., 1994; Chait and

Burke, 1994; Chait and Pierri, 1992; Foltin et al., 1990; Cone et al.,

1988; Mendelson and Mello, 1984). Marijuana also serves as a

discriminative stimulus in humans and produces euphoria and alterations

in mood. These subjective changes were used by the subjects as the

basis for the discrimination from placebo (Chait et al., 1988).

    In addition, smoked marijuana administration resulted in multiple

brief episodes of euphoria that were paralleled by rapid transient

increases in EEG alpha power (Lukas et al., 1995);

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these EEG changes are thought to be related to CNS processes of

reinforcement (Mello, 1983).

    To help elucidate the relationship between the rise and fall of

plasma THC and the self-reported psychotropic effects, Harder &

Rietbrock (1997) measured both the plasma levels of THC and the

psychological “high” obtained from smoking a marijuana cigarette

containing 1% THC. As can be seen from these data, a rise in plasma THC

concentrations results in a corresponding increase in the subjectively

reported feelings of being “high”. However, as THC levels drop the

subjectively reported feelings of “high” remain elevated. The

subjective effects seem to lag behind plasma THC levels. Similarly,

Harder and Rietbrock compared lower doses of 0.3% THC-containing and

0.1% THC-containing cigarettes in human subjects.

    As can be clearly seen by these data, even low doses of marijuana,

containing 1%, 0.3% and even 0.1% THC, typically referred to as “non-

active”, are capable of producing subjective reports and physiological

markers of being “high’.

    THC and its major metabolite, 11-OH-THC, have similar psychoactive

and pharmacokinetic profiles in man ( Wall et al., 1976; DiMarzo et

al., 1998; Lemberger et al., 1972). Perez-Reyes et al. (1972) reported

that THC and 11-OH-THC were equipotent in generating a “high” in

human volunteers. However, the metabolite, 11-OH-THC, crosses the

blood-brain barrier faster than the parent THC compound (Ho et al.,

1973; Perez-Reyes et al., 1976). Therefore, the changes in THC plasma

concentrations in humans may not be the best predictive marker for the

subjective and physiological effects of marijuana in humans. Cocchetto

et al. (1981) have used hysteresis plots to clearly demonstrate that

plasma THC concentration is a poor predictor of simultaneous occurring

physiological (heart rate) and psychological (“high”) pharmacological

effects. Cocchetto et al. demonstrated that the time course of

tachycardia and psychological responses lagged behind the plasma THC

concentration-time profile. As recently summarized by Martin & Hall

(1997, 1998)

    There is no linear relationship between blood [THC] levels and

pharmacological effects with respect to time, a situation that

hampers the prediction of cannabis-induced impairment based on THC

blood levels (p90).

Physical Dependence in Animals

    There are reports that abrupt withdrawal from

9-THC can produce a mild spontaneous withdrawal

syndrome in animals, including increased motor activity and grooming in

rats, decreased seizure threshold in mice, increased aggressiveness,

irritability and altered operant performance in rhesus monkeys (cf.,

Pertwee, 1991). The failure to observe profound withdrawal signs

following abrupt discontinuation of the drug may be due to

9-THC’s long half-life in plasma and slowly waning

levels of drug that continue to permit receptor adaptation.

    Recently the discovery of a cannabinoid receptor antagonist

demonstrates that a profound precipitated withdrawal syndrome can be

produced in 9-THC tolerant animals after twice

daily injections (Tsou et al., 1995) or continuous infusion (Aceto et

al., 1995, 1996).

Physical Dependence in Humans

    Signs of withdrawal in humans have been demonstrated after studies

with marijuana and 9-THC. Although the intensity of

the withdrawal syndrome is related to the daily dose and frequency of

administration, in general, the signs of 9-THC

withdrawal have been relatively mild (cf., Pertwee, 1991). This

withdrawal syndrome has been compared to that of short-term, low dose

treatment with opioids, sedatives, or ethanol, and includes changes in

mood, sleep, heart rate, body temperature, and appetite. Other signs

such as irritability, restlessness, tremor, mild nausea, hot flashes

and sweating have also been noted (cf., Jones, 1980, 1983).

    Chait, Fischman, & Schuster (1985) have demonstrated an acute

withdrawal syndrome or “hangover” occurring approximately 9 hours

after a single marijuana smoking episode. Significant changes occurred

on two subjective measures and on a time production task. In 1973,

Cousens & DiMascio reported a similar “hangover” effect from acute

administrations of 9-THC. The hangover phenomenon

or continued “high”, in the Cousens & DiMascio study, occurred 9 hrs

after drug administration and was associated with some residual

temporal disorganization, as well. These residual or hangover effects

may mimic the withdrawal syndrome, both qualitatively and

quantitatively, which is expressed after chronic marijuana exposure.

This acute hangover may reflect a true acute withdrawal syndrome

similar to that experienced from high acute alcohol intake. The

presence of an acute withdrawal syndrome after drug administration has

been suggested to represent a physiological compensatory rebound by

which chronic administration of the drug will eventually potentiate and

produce dependence and the potential for continued abuse (Gauvin, Cheng

& Holloway, 1993).

    Crowley et al. (1998) screened marijuana users for DSM-IIIR

dependence criteria. Of the 165 males and 64 female patients that met

the criteria, 82.1% were found to have co-morbid conduct disorders;

17.5% had major depression; and 14.8% had a diagnosis of attention-

deficit/hyperactivity disorder. These results also showed that most

patients claimed to have “serious problems” from cannabis use. The

data also indicated that for adolescents with conduct problems,

cannabis use was not benign, and that the drug served as a potent

reinforcer for further cannabis usage, producing dependence and

withdrawal.

    Kelly & Jones (1992) quantified concentrations of THC and its

metabolites in both plasma and urine after a 5 mg intravenous dose of

THC was administered to frequent and infrequent marijuana smokers. The

frequent smokers were users who smoked marijuana almost daily for at

least two years. The infrequent smokers were users who smoked marijuana

no more than two to three times per month but had done so for at least

two years. Pharmacokinetic parameters after intravenously administered

THC revealed no significant differences between frequent and infrequent

marijuana users on area under the time-effect curve (AUC), volume of

distribution, elimination half-lives of parent THC and metabolites in

plasma and urine. There were also no group differences in metabolic or

renal clearances. The authors concluded that there was no evidence for

metabolic or dispositional tolerance between the two groups of

subjects. Kelly and Jones also reported that tolerance was not evident

in heart rate, diastolic blood pressure, skin temperature, and the

degree of psychological “high” from the i.v. administration of THC.

    In two separate reports, Haney et al. have recently described

abstinence symptoms of an acute withdrawal syndrome following high (30

mg q.i.d.) and low (20 mg q.i.d) dose administrations of oral THC

(Haney et al., 1999a) and following 5 puffs of high (3.1%) and low

(1.8%) THC-containing smoked marijuana cigarettes (Haney et al.,

1999b). Abstinence from oral THC increased ratings of “anxious”,

“depressed”, and “irritable”, and decreased the reported quantity

and quality of sleep and decreased food intake by 20-30% compared to

baseline. Abstinence from as low as 5 controlled puffs of active

marijuana smoking increased ratings of “anxious”, “irritable” and

“stomach pain”, and

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significantly decreased food intake. The 5 controlled puffs of 5 second

duration each were drawn from 2 separate marijuana cigarettes (3 puffs

from one, 2 puffs from the other. The smoke was held for 40 seconds and

then exhaled. All subjects reported significant increases on subjective

measures of “high”, “good drug effect”, and “stimulated”, as well

as “mellow”, “content”, and “friendly” as a result of this

limited and controlled draw of THC. Both of these studies have

delineated a withdrawal syndrome from concentrations of THC

significantly lower than those reported in any other previous study

and, for the first time, clearly identified a marijuana withdrawal

syndrome detected at low levels of THC exposure that do not produce

tolerance. The abstinence syndrome was not limited to subjective state

changes but was also quantified using a cognitive/memory test battery.

    In a related study, Khouri et al (1999) found that long-term heavy

marijuana users became more aggressive during abstinence from marijuana

than did former or infrequent users. Previous dependence studies have

relied largely on patients’ subjective reports of a range of symptoms.

Khouri et al. examined a single symptom–aggression. The authors

concluded that marijuana abstinence is associated with unpleasant

behavioral symptoms that may contribute to continued marijuana use.

    Kouri & Pope (2000) examined three groups of marijuana users during

a 28-day supervised abstinence period. Current marijuana users

experienced significant increases in anxiety, irritability, physical

tension, and physical symptoms and decreases in mood and appetite

during marijuana withdrawal. These symptoms were most pronounced during

the initial 10 days of abstinence, bust some were present for the

entire 28-day withdrawal period. The findings from this study reveal

that chronic heavy users of marijuana experience a number of withdrawal

symptoms during abstinence and clearly demonstrate a “marijuana

dependence syndrome” in humans.

    These data suggest that dependence on THC may in fact be an

important consequence of repeated, daily exposure to cannabinoids and

that daily marijuana use may be maintained, at least in part, by the

alleviation of abstinence symptoms. Relevant to the present petition,

the Haney et al. study is the first report demonstrating this syndrome

with extremely low concentrations of THC.

Results of THC Dose Comparison Studies

    There are reports in the scientific literature that evaluated dose-

related subjective and reinforcing effects of Cannabis sativa in

humans. These studies have assessed the subjective and reinforcing

effects of cannabis cigarettes containing different potencies of THC

and/or which have manipulated the THC dose by varying the volume of THC

smoke inhaled (Azorlosa et al., 1992; Lukas et al., 1995; Chait et al.,

1988; Chait and Burke, 1994; Kelly et al., 1993).

    Chait et al. (1988) studied the discriminative stimulus effects of

smoked marijuana cigarettes containing THC contents of 0%, 0.9%, 1.4%,

2.7%. Marijuana smokers were trained to discriminate smoked marijuana

from placebo using 4 puffs of a 2.7%-THC cigarettes. Subjective ratings

of “high”, and physiological measures (i.e., heart rate) were

significantly and dose-dependently increased after smoking the 0.9%,

1.4%, 2.7%.

    Marijuana cigarettes containing 1.4% THC completely substituted for

2.7%-THC on drug identification tasks, however, 0.9%-THC did not. The

authors found that the onset of discriminative stimulus effects was

within 90 seconds after smoking began (after the first two puffs).

Since the 1.4%-THC cigarette substituted for 2-puffs of the 2.7%-THC

cigarette, the authors estimate that an inhaled dose of THC as low as 3

mg can produce discriminable subjective effects.

    Similarly, Lukas et al. (1995) reported that marijuana cigarettes

containing either 1.26% or 2.53% THC produced significant and dose-

dependent increases in level of intoxication and euphoria in male

occasional marijuana smokers. Four of the six subjects that smoked the

1.26%-THC cigarette reported marijuana effects and 75% of these

subjects reported euphoria. All six of the subjects that smoked 2.53%

THC reported marijuana effects and euphoria. Peak levels of self-

reported intoxication occurred at 15 and 30 minutes after smoking and

returned to control levels by 90-105 minutes. There was no difference

between latency to or duration of euphoria after smoking either the

1.26% or 2.53% THC cigarettes. The higher dose-marijuana cigarette

produced a more rapid onset and longer duration of action than the

lower dose marijuana cigarette (1.26% THC). Plasma THC levels peaked 5-

10 minutes after smoking began; the average peak level attained after

the low- and high-dose marijuana cigarette was 36 and 69 ng/ml

respectively.

    In order to determine marijuana dose-effects on subjective and

performance measures over a wide dose range, Azorlosa et al. (1992)

evaluated the effects of 4, 10, or 25 puffs from marijuana cigarettes

containing 1.75 or 3.55% THC in seven male moderate users of marijuana.

Orderly dose-response curves were produced for subjective drug effects,

heart rate, and plasma concentration, as a function of THC content and

number of puffs. After smoking the 1.75% THC cigarette, maximal plasma

THC levels were 57 ng/ml immediately after smoking, 18.3 ng/ml 15

minutes after smoking, 10.3 ng/ml 30 minutes after smoking, and 7.7 ng/

ml 45 minutes after smoking.

    The study also showed that subjects could smoke more of the low THC

cigarette to produce effects that were similar to the high THC dose

cigarette (Azorlosa et al., 1992). There were nearly identical THC

levels produced by 10-puff low-THC cigarette (98.6 ng/ml) and 4-puff

high THC cigarette (89.4 ng/ml). Similarly, the subjective effects

ratings, including high, stoned, impaired, confused, clear-headed and

sluggish, produced under the 10 puff low- and high-THC and 25 puff low-

THC conditions did not differ significantly from each other.

    As with most drugs of abuse, higher doses of marijuana are

preferred over lower dose. Although not preferred, these lower doses

still produce cannabimimetic effects. Twelve regular marijuana smokers

participated in a study designed to determine the preference of a low

potency (0.64%-THC) vs. a high potency (1.95%-THC) marijuana cigarette

(Chait and Burke, 1994). The subjects first sampled the marijuana of

two different potencies in one session, then chose which potency and

how much to smoke. During sampling sessions, there were significant

dose-dependent increases in heart rate and subjective effects,

including ratings of peak “high”, strength of drug effects,

stimulated, and drug liking. During choice sessions, the higher dose

marijuana was chosen over the lower dose marijuana on 87.5% of

occasions. Not surprising, there was a significant positive correlation

between the total number of cigarettes smoked and the ratings of

subjective effects, strength of drug effect, drug “liking”, expired

air carbon monoxide, and heart rate increases. The authors state it is

not necessary valid to assume that the preference observed in the

present study for the high-potency marijuana was due to greater CNS

effects from its higher THC content. The present study found that the

low- and high-potency marijuana cigarettes also differ on

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several sensory dimensions; the high-potency THC was found to be

reported as “fresher” and “hotter”. Other studies found that

marijuana cigarettes containing different THC contents varied in

sensory dimensions (cf., Chait et al., 1988; Nemeth-Coslett et al.,

1986).

    As summarized by Martin & Hall for the United Nations only a small

amount of cannabis (e.g. 2-3 mg of available THC) is required to

produce a brief pleasurable high for the occasional user and a single

joint may be sufficient for two or three individuals. Using these data

and those of Harder & Reitbroch (1997, above), a one gram cigarette

containing 1% THC containing cannabis, would contain 10 mg of THC–a

dose well capable of producing a social high.

    Carlini et al. (1974) examined 33 subjects who smoked marijuana

cigarettes with different ratios of constituent cannabinoids. The plant

containing 0.82% THC produced larger than expected results based on the

estimates from the THC content.

    Smoking a 250 mg cigarette containing 5.0 mg of

9-THC induced more reactions graded 3 and 4 than 10

or 20 mg of 9-THC. It was further observed that the

psychological effects (subjective “high”) started around 10 min after

the end of the inhalation, and reached a maximum 20 to 30 min later,

subsiding within 1 to 3 hrs. The peak of psychological disturbances,

therefore, did not coincide in time with the peak of pulse rate

effects. Carlini et al., suggested that other constituents of the

marijuana were interacting synergistically with the THC to potentiate

the subjective response induced by the smoking of the cigarette.

Karniol and colleagues (1973, 1974) have clearly demonstrated that

cannabidiol (CBD) blocks some of the effects induced by THC, such as

increased pulse rates and disturbed time perception. More importantly,

CBD blocked some of the psychological effects of THC, but not by

altering the quantitative or intensity of the psychological reactions.

CBD seemed better able to block the aversive effects of THC. CBD

changed the symptoms reported by the subjects in such a way that the

anxiety component produced by THC administration was actually reduced.

The animal subjects of one study showed greater analgesia scores with a

CBD+THC combination (1973) and the human subjects from the other study

(1974) showed less anxiety and panic but reported more pleasurable

effects. CBD may be best seen as an “entourage” compound (Mechoulam,

Fride, DiMarzo, 1998) which is administered along with THC and results

in a functional potentiation of THC’s behavioral and subjective

effects. This potentiation can be in both the intensity and/or duration

of the high induced by marijuana. According to Paris & Nahas (1984) the

CBD:THC ratio in industrial or fiber type hemp is 2:1. Relevant to the

current petition, the CBD:THC ratio producing the greatest increase in

euphoria in the Karniol, et al. studies was 2:1 (60:30 mg).

    Jones & Pertwee (1972) were first to report that the presence of

cannabidiol inhibited the metabolism of THC and its active metabolite.

These data were soon replicated by Nilsson et al., (1973). Bronheim et

al., (1995) examined the effects of CBD on the pharmacokinetic profile

of THC content in both blood and brains of mice. CBD pretreatments

produced a modest elevation in THC-blood levels; area under the

kinetics curve of THC was increased by 50% as a function of decreased

clearance. CBD pretreatments also modestly increased the

Cmax, AUC, and half-life of the major THC metabolites in the

blood. The THC kinetics function showed a 7- to 15-fold increase in the

area under the curve, a 2- to 4-fold increase in the half-life, as well

as the tmax. CBD pretreatments resulted in large increases

in area under the curves and half-lives of all the THC metabolites in

the mice brains. The inhibition of the metabolism of THC and its

psychoactive metabolites by CBD may underlie the potentiation in the

subjective effects of THC by CBD in humans.

    In addition to THC, hemp material contains a variety of other

substances (e.g., Hollister, 1974), including other cannabinoids such

as cannabidiol (CBD) and cannabinol (CBN). One comprehensive review

described the activities of 300 cannabinoid compound in preclinical

models (Razdan, 1986). Since CBD is always present in preparations of

cannabis, it may represent a high CBD:THC ratio in the case of low THC

cannabis. Therefore, it is important to understand the interactions of

cannabidiol and 9-THC.

    Structure-activity studies of cannabinoid compounds characterized

cannabidiol in relationship to 9-THC and other

cannabinoids (Martin et al., 1981; Little et al., 1988). These and

other studies have found that cannabidiol was inactive and did not

produce neuropharmacological effects or discriminative stimulus,

subjective effects and behavioral effects predictive of psychoactive

subjective effects (Howlett, 1987; Howlett et al., 1992; c.f., Hiltunen

and Jarbe, 1986; Perez-Reyes et al., 1973; Zuardi et al., 1982; Karniol

et al., 1974).

    Other studies have reported that cannabidiol has cannabinoid

properties, including anticonvulsant effects in animal and human models

(Consroe et al., 1981; Carlini & Cunha, 1981; Doyle and Spence, 1995),

hypnotic effects (Monti, 1977), anxiolytic effects (Musty, 1984;

Onaivi, Geen, & Martin, 1990; Guimarares et al., 1990; 1994) and rate-

decreasing effects on operant behavior (Hiltunen et al., 1988).

    Experiments with cannabidiol in combination with THC have found

that certain behavioral responses induced by THC (i.e., operant,

schedule-controlled responding) were attenuated by cannabidiol (Borgen

and Davis, 1974; Brady and Balster, 1980; Consroe et al., 1977; Dalton

et al., 1976; Kraniol and Carlini, 1973; Karniol et al., 1974; Welburn

et al., 1976; Zuardi and Karniol, 1983; Zuardi et al., 1981, 1982;

Hiltunen et al., 1988). However, other affects produced by THC are

augmented or prolonged by the combined administration of CBD and THC or

marijuana extract (Chesher and Jackson, 1974; Hine et al., 1975a,b;

Fernandes et al., 1974; Karniol and Carlini, 1973; Musty and Sands,

1978; Zuardi and Karniol, 1983; Zuardi et al., 1984). Still other

studies did not report any behavioral interaction between the CBD and

THC (Bird et al., 1980; Browne and Weissman, 1981; Hollister and

Gillespie, 1975; Jarbe and Henricksson, 1974; Jarbe et al., 1977;

Mechoulam et al., 1970; Sanders et al., 1979; Ten Ham and DeLong,

1975).

    A study to characterize the interaction between CBD and THC was

conducted using preclinical drug discrimination procedures. Rats and

pigeons trained to discriminate the presence or absence of THC, and

tested with CBD administered alone and in combinations with THC

(Hiltunen and Jarbe, 1986).

    Specifically, in rats trained to discriminate 3.0 mg/kg, i.p. THC,

CBD (30.0 mg/kg) was administered alone and in combination with THC

(0.3 and 1.0 mg/kg, i.p.). In pigeons trained to discriminate 0.56 mg/

kg, i.m. THC, CBD (17.5 mg/kg) was administered alone and in

combination with THC (0.1, 0.3, and 0.56 mg/kg, i.m.). CBD prolonged

the discriminative stimulus effects of THC in rats, but did not change

the time-effect curve for THC in pigeons. In pigeons, the

administration of CBD did not produce any differential effect under a

fixed ratio schedule of reinforcement (Hiltunen and Jarbe, 1986).

    These data suggest that CBD may somehow augment or prolong the

actions of THC in rats and had no effect in pigeons. In the present

study, the CBD/THC ratios ranged from 30:1 to 100:1 in rats and

enhanced the stimulus

[[Page 20058]]

effects of THC. However, similar CBD/THC ratios in pigeons (31:1, 58:1

and 175:1) did not result in any changes to THC’s discriminative

stimulus or response rate effects (Hiltunen and Jarbe, 1986).

    It should be noted that cannabidiol can be easily converted to

delta-9- and delta-8-tetrahydrocannabinol. Even industrial hemp plant

material (leaves), containing high concentrations of CBD, can be

treated in clandestine laboratories to convert the CBD to delta-9-

tetrahydrocannabinol (Mechoulam, 1973) converting a supposedly

innocuous weed into a potent smoke product.

    In conclusion, the “entourage” compound, cannabidiol, does

contribute to all of the effects ascribed to THC, however it also

appears to lack cannabimimetic properties. However, there is no

credible scientific evidence that CBD is a pharmacological antagonist

at the cannabinoid receptor (Howlett, Evans, & Houston, 1992). There is

clear evidence that CBD can functionally antagonize some of the

aversive effects of THC (Dewey, 1986). The data from the scientific

literature cited above, clearly demonstrate the ability of CBD to

modify some very specific effects of THC. Most importantly, relative to

the euphorigenic effects of THC (which contributes to its abuse

liability), CBD appears to potentiate the psychological or subjective

effects of THC by potentiating the blood and brain THC and 11-OH-THC

levels and by functionally blocking the aversive (anxiety-like)

properties of THC.

Abuse Liability Summary

    Preclinical and clinical experimental data demonstrate that

marijuana and “9-THC have similar abuse

liabilities (i.e., drug discrimination, self-administration, subjective

effects). Both preclinical and clinical studies show that

discontinuation of either marijuana or “9-THC

administration produces a mild withdrawal syndrome. The effects of THC

are dose-dependent and several studies have found that low-potency THC

is behaviorally active and can produce cannabimimetic-like subjective

and physiological effects.

Actual Abuse

    There are dozens of data collection and reporting systems that are

useful for monitoring the United States’ problem with abuse of licit

and illicit substances. These data collection and reporting systems

provide quantitative data on many factors related to abuse of a

particular substance, including incidence, pattern, consequence and

profile of the abuser of specific substances (cf., Larsen et al.,

1995).

    Evidence of actual abuse is defined by episodes/mentions in the

databases indicative of abuse/dependence. Some of the databases that

are utilized by DEA to provide data relevant to actual abuse of a

substance include the Drug Abuse Warning Network (DAWN), National

Household Survey on Drug Abuse, Monitoring the Future survey, FDA’s

Spontaneous Adverse Events Reports, the American Association of Poison

Control Centers database and reports of the Community Epidemiology Work

Group (CEWG).

    Drug trafficking and diversion data provide strong evidence that a

drug or other substance is being abused. In order to determine the

pattern, incidence, and consequences of abuse and the demographics of

abusers of a particular substance to be controlled, DEA relies on data

collected from a number of sources, including the United States

government as well as state and local law enforcement groups.

Information from these sources often provides a first indication of an

emerging pattern of abuse of a particular drug or substance, and when

taken together with other data sources provide strong evidence that can

be used in determining a substance’s placement in the schedules listed

in the CSA.

    The evidence from epidemiological studies conclude that marijuana

use alone and in combination with other illicit drugs is increasing.

The most recent “Monitoring the Future Study”, documented increases

in lifetime, annual and current (within the past 30 days) and daily use

of marijuana by eighth and tenth graders; this increasing trend began

in the early 1990’s.

    Similarly, according the NIDA’s “National Household Survey”,

marijuana use is increasing with the greatest increase among the

younger age groups (12-17 years of age). The frequency of marijuana use

in the past year increases significantly among 12-17 year olds. This

survey also found that youths who used marijuana at least once in their

lives were more likely to engage in violent or other antisocial

behaviors.

    Marijuana is the most readily available illicit drug in the United

States. Cannabis is cultivated in remote locations and frequently on

public lands. Major domestic outdoor cannabis cultivation areas are

found in California, Hawaii, Kentucky, New York and Tennessee.

Significant quantities of marijuana were seized from indoor cultivation

operations; there were 3,532 seizures in 1996 compared to 3,348 seized

in 1995. Mexico is the major source of foreign marijuana, along with

lesser amounts from Colombia and Jamaica (NNICC, 1996).

    Domestically, marijuana is distributed by groups or individuals,

ranging from large sophisticated organizations with controlled

cultivation and interstate trafficking, to small independent

traffickers at the local level.

(2) Scientific Evidence of Its Pharmacological Effects, If Known

    Cannabis sativa is unique in that it is the only botanical source

of the terpenophenolic substances referred to as cannabinoids which are

responsible for the psychoactive effects of Cannabis. There are roughly

60 different cannabinoids found in Cannabis (Nahas, 1984; Murphy &

Bartke, 1992; Agurell, Dewey & Willette, 1984) but the psychoactive

properties of Cannabis are attributed to one or two of the major

cannabinoid substances, namely delta-9-tetrahydrocannabinol and delta-

8-tetrahydrocannabinol. In fresh, carefully dried marijuana, up to 95%

of their cannabinoids are present as (-)-delta-9-(trans)-

tetrahydrocannabinol carboxylic acid (Nahas, 1984; Murphy & Bartke,

1992; Agurell, Dewey & Willette, 1984). The acid form is not

psychoactive, but is readily decarboxylated upon heating to yield

delta-9-tetrahydrocannabinol (neutral form). Therefore, plant material

could be very high in its “pro-drug” acid form and very low in

neutral form but still be very potent when smoked.

    There are two primary factors that influence THC content: genetic

predisposition and environmental influences. Genetic factors are

considered predominant in determining cannabinoid content, although,

fluctuations in weather conditions have greatly enhanced or diminished

the THC content.

    Paris & Nahas (1984) have admonished that marijuana is not a single

uniform plant like many of those encountered in nature, but a rather

deceptive weed with several hundred variants. The intoxicating

substances prepared from Cannabis vary considerably in potency

according to the varying mixtures of different parts of the plant, and

according to the techniques of fabrication. According to Paris & Nahas,

this basic botanical fact has been overlooked by physicians and

educators, who have written about marijuana as a simple, single

substance, which uniformly yields a low concentration of a single

intoxicant. In addition to changes due to its own genetic plasticity,

marijuana has been modified throughout the ages by environmental

factors and human manipulations, and is not yet a

[[Page 20059]]

stabilized botanical species (Paris & Nahas, 1984).

    According to Paris & Nahas (1984) the terminology used by Fetterman

et al. (1970, 1971) is somewhat misleading, especially with respect to

their contention that environmental factors, including climate, are not

as important as heredity in determining the cannabinoid content of

cutigens. The analyses of Fetterman et al., (1970) were performed

according to the technique by Doorenbos et al., (1971) on plant

materials from variants that had been cut at the stem beneath the

lowest leaves and air-dried. Seeds, bracts, flowers, leaves and small

stems were then stripped from the plant. Most of the small stems were

removed by a 10-mesh screen, and the seeds were eliminated with a

mechanical seed separator. This preparation of marijuana contains less

seed and stem than most of the illicit material available in the United

States. Cannabinoids were then extracted from the plant material and

analyzed by standard techniques.

    Other systems of separating Cannabis into drug, intermediate and

non-drug type have been developed. These are typically determined by

chemical analyses based upon the method described by Doorenbos (1971)

which utilizes manicured portions of the Cannabis plant only in

determining percent concentration.

    Cannabis sativa has been referred to as a widely distributed and

unstabilized species. Cannabis exhibits extreme polymorphism (ability

to alter, change) in different varieties, dependent upon many factors.

For example, there are at least twenty strains which are cultivated for

fiber. There have been many attempts to classify Cannabis as a function

of intoxicant properties or fiber properties. Such classification

efforts are dependent upon the age of the sample. And there is no

totally reliable classification system based on a single chemical

analysis. The plasticity of the genus has prevented the development of

such a system (Turner et al. 1980a,b).

    In a study where twelve strains of Cannabis were grown out of doors

in Southern England (Fairbairn and Liebmann, 1974, Fairbairn et al.,

1971), the following were determined:

1. Warm climate are not necessary for high THC content.
2. There is considerable THC content variation within and between

plants.

3. Quantitative results of tetrahydrocannabinol concentration (THC)

are highly dependent upon the specific plant part sampled, the stage of

growth and the size of sample.

4. Certain strains of Cannabis can be THC or cannabidiol (CBD) rich

which does not seem to be dependent upon environmental conditions.

5. However, growing the same strain of Cannabis under different

lighting conditions can produce plants that range from 2.4 to 4.42% THC

concentration (based upon an analysis of the upper leaves). And

finally,

6. THC concentration are dramatically higher on dried flowering or

vegetative tops of the plants relative to middle or lower portions.

    In a similar study on the characterization of Cannabis accessions

with regard to cannabinoid content, vis-a-vis other plant characters

(deMeijer, 1992), it was determined that:

1. There exists considerable variation within and among accessions

for cannabinoid content;

2. Mean cannabinoid content is strongly affected by year of

cultivation;

3. There is no strict relationship between chemical and non-

chemical traits; and,

4. It is uncommon, but some accessions combine high bark fiber

content and considerable psychoactive potency.

    In 1993 de Meijer reported the results of a government

(Netherlands) funded industrial hemp project designed to investigate

the stem quality, yield, and a comparative analysis to wood fibers.

deMeijer found that the commercial grade industrial hemp seeds,

germplasms derived from 0.3% THC chemovars, demonstrated a significant

variation in the average THC content which ranged from 0.06 to 1.77% in

the female dry leaf matter. deMeijer concluded by stating,

    Although high bark fiber content does not necessarily exclude

high THC content, most fiber cultivars have very low THC content and

thus possess no psychoactive potency

While the data from his own study refutes these conclusions he does

conclude that the industrial hemp plant does not preclude high THC

content.

    A review of these and other studies in the scientific literature,

indicate that THC concentrations vary within portions of the Cannabis

plant (Hanus et al., 1989, 1975). In some studies, the concentration of

THC can increase as much as 100% from leafy to flowering portions of

the same plant. THC concentrations are known to be elevated on the

upper portions of the plant. In a study published by Fairbairn and

Liebmann, (1974) there was considerable variations between the

flowering tops (bracts, flowers, immature fruits at the ends of shoots)

and leafy portions of some specimens. THC content decreases with age

and length of leaves (Paris & Nahas, 1984, p 25). The lower, more

developed leaves have a low cannabinoid content and the top leaves have

a high cannabinoid content, especially when they are associated with

the bracts of the plant. Cannabinoids are localized in the upper third

of the “stalk” and in the flowers. Therefore, the THC content of

specific portions of a plant, which on a whole plant basis did not

exceed 1%, could significantly exceed this threshold. Very few

marijuana users actually “smoke” the leaves. It is the colas or the

flowering portions of the plants which are utilized and these are

exactly the portions of the plant which would be expected to have the

highest concentration of THC.

    It is clearly recognized that Cannabis presents a high degree of

genetic plasticity which results in extreme polymorphism in its

different varieties. The hemp first grown in the United States for

fiber was of European origin. The type basic to modern American fiber

production, known as Kentucky, came originally from China. In Europe,

there are five to six varieties with one considered “exceptional”–

the Kymington. The plasticity of the European fiber variety has been

clearly shown (Bouquet, 1951; Hamilton, 1912, 1915). European cultigens

planted in dry, warm areas of Egypt to supply fiber for rope-making

were found to produce, within several generations, plants with high

psycho-active ingredients and very little fiber. Cannabis sativa’s

botanical and chemical characteristics change markedly as a result of

environmental factors and human manipulation. Doorenbos et al., (1971)

cultivated a Mexican and Turkish variant in Mississippi for three

consecutive generations. During that period, the 9-

THC content did not change in the Mexican variant but increased in the

Turkish variant. In the more controlled environment of a phytotron

(light, humidity, and nutrition controlled), Braut-Boucher (1978),

Braut-Boucher & Petiard (1981), Braut-Boucher, Paris, & Cosson (1977)

and Paris et al., (1975) found that the cannabinoid concentrations rose

over a similar three year period. The concentrations rose more sharply

in cool environments (22-12 deg.C: day-night) than in warm environments

(32-12 deg.C). Some authors have hypothesized that immediate

environmentally caused changes are individual plant reactions, whereas

the progressive changes over generations are linked with whole

populations and constitute a true natural selection. Whether this

evolution is caused by a change of genetic equilibrium (caused by the

environment), or by a

[[Page 20060]]

modification of the genetic capacity (over time), is impossible to say

(Paris & Nahas, 1984).

    In 1974 through 1976 the University of Mississippi cultivated 7

variants of 12 Cannabis plants discovered and collected in 1973 from

different areas of Mexico. Cannabinoid content was analyzed weekly

during the cultivation period. Turner, Elsohly, Lewis, Lopez-Santibanez

& Carranza (1982) summarized their findings as follows:

    In 1974, vegetative plants of ME-H, ME-K, ME-L, ME-N and ME-O,

at 13 weeks of age had higher 9-THC content that

at weeks 12 and 14. They showed minimum 9-THC

content at week 15. For the most part, 1974 staminate and pistillate

plants grown in Mississippi produced a low 9-THC

concentration * * *.

    In all variants, the average 9-THC was higher

in 1976 than in 1974. Also, a greater fluctuation of

9-THC was observed in 1976 than in 1974.

    These results further establish that Cannabis Sativa L. is not a

stable hybrid plant, but rather, represents characteristics more

similar to an unstable weed.

    Marijuana chemistry is complex and cannot be simplified or

extrapolated from any one or two “active compounds”. As early as 1974

this fact was recognized by the United Nations Division on Narcotic

Drugs (UN Doc, 1974). As highlighted by Turner (1980), the chemistry of

THC is not the chemistry of marijuana and the pharmacology of marijuana

is not the pharmacology of THC. Recent findings do suggest that the

interactions between cannabinoids is one of many critical factors in

the analysis of the psychopharmacology of marijuana.

    According to Jones (1980), because of exposure to a wide range of

plant material and the cultural labeling (almost like advertising) of

much of the marijuana experience, marijuana users are particularly

subject to the effects of nonpharmacological variables that alter the

subjective response to marijuana intoxication (Jones 1971, 1980;

Cappell & Pliner, 1974; Becker 1967). As reviewed by Jones (1971), a

number of studies suggest that experienced marijuana users are more

subject to “placebo reactions’; that is, a degree of intoxication

disproportionate to the THC content of the material. This seems

particularly true if the individuals are exposed to low potency

marijuana (1.0% THC). Jones believes that this is a result of

experience and practice at recognizing minimal physiologic cues

together with the smell, taste and other sensations associated with

smoking a marijuana cigarette (Jones 1980, 1971). Becker 1967 and

Cappell & Pliner (1974) have described a number of psychological

factors (expectancy, social setting, etc.) that appear to

synergistically interact to help generate the subjective experiences

engendered by marijuana smoking.

    Domino, Rennick, & Pearl (1976) administered THC injected into

tobacco cigarettes to male volunteers. Similar to findings described by

Isbell et al., (1967) they report that 50 g of THC into the

cigarettes produced a “social high”, while 250 g/kg was

“hallucinogenic”. Taking 80 kg as the mean weight of their subjects

the authors concluded that a 4.0 mg total THC dose produced a “social

high”; a hallucinogenic dose was 20 mg total THC by inhalation. A

standard 1g cigarette of 1% THC fibre-type hemp provides 10 mg of THC.

Even allowing for a 50% loss of THC from sidestream smoke and

pyrolysis, smoking this cigarette provides more than enough THC to

produce a “social high”.

    In 1968 Weil, Norman, & Nelsen described a set of studies examining

the physiological and psychological aspects of smoked marijuana. The

first batch of Mexican grown marijuana used in the study was found to

contain only 0.3% THC by weight. The potency of this product was

considered to be “low” by the experimenters on the basis of the doses

needed to produce symptoms of intoxication in the chronic users. This

low potency marijuana was able to produce a “high”, but only with two

1 gram cigarettes. A second batch was used in later studies. Weil,

Norman, & Nelsen report that marijuana assayed at 0.9% THC (a quantity

slightly less than the 1% THC limit set forth by the petitioners) was

rated by the chronic users in the study to be “good, average”

marijuana, neither exceptionally strong nor exceptionally weak compared

to the usual supplies. Users consistently reported symptoms of

intoxication after smoking about 0.5 grams of the 0.9% THC containing

marijuana (half a joint). With the high dose of marijuana (2.0 grams of

0.9% THC containing marijuana) all chronic users became “high” by

their own accounts and in the judgment of experimenters who had

observed many persons under the influence of marijuana.

    Agurell & Leander (1971) examined the physiological and

psychological effects of low THC-containing cannabis in experienced

users. They reported that 14-29% of the cannabinoid content of the

cigarette was transferred to the main stream smoke. Based on

qualitative and quantitative analyses, Agurell & Leander demonstrated

that as little as 3-5 mg of THC was needed to be absorbed by the lung

in order to produce a “normal biological high”. Further, they found

that as little as 1 mg of absorbed THC was discriminable by all of

their chronic user subjects.

    In 1982, Barnett, Chiang, Perez-Reyes, & Owens had six subjects

smoke a 1% THC-containing (industrial hemp, as defined by the

petitioner) marijuana cigarette. Significant heart rate and subjective

measures of “high” were measured for 2 hours after each cigarette.

    In 1971 Jones reported on the wide variability in THC

concentrations found in street samples:

    Specimens gathered in the midwestern United States contained

only 0.1–0.5% THC. Thirty specimens selected from seized samples in

the Bureau of Narcotics and Dangerous Drugs Laboratory in San

Francisco all contained less than 1% THC. Samples from the State of

California Bureau of Narcotic enforcement analyzed in our laboratory

contained as little as 0.1% THC and a maximum of 0.9% * * * In a

survey done in Ontario, Canada, Marshman and Gibbons found that of

36 samples alleged to be marijuana with high cannabinoid content,

34% contained no marijuana at all, and much of the rest was cut with

other plant substances. A generous assumption is that marijuana

generally available in the United States averages about 1.0% THC.

    It must be acknowledged that the THC content of domestically grown

and imported marijuana has increased since these reports. However, the

description by Weil, Zinberg & Nelson (1968), Agurell & Leander (1971),

Jones (1971) and Barnett et al. (1982) highlight the historical

importance of low THC concentrations contained in marijuana which

provided the basis for the marijuana culture that developed in the

1970s. The incident described by Jones was not an isolated case of the

inadvertent misrepresentation of the THC content of marijuana extracts.

Caldwell et al., (1969) found that the NIMH-supplied marijuana that

they reported to have contained 1.3% THC was analyzed by two

independent laboratories and found to contain as little as 0.2 to 0.5%

THC. Similarly, according to Paton & Pertwee (1973) the THC content of

material used by Clark & Nakashima (1968), Weil et al., (1968), Weil &

Zinberg (1969), and Crancer et al., (1969) must be expected to be one-

third to one-sixth less than stated. This means that the positive

results of all of these studies were the result of a surprisingly low

THC-containing (1.0%) marijuana. The early scientific data on the

subjective effects of marijuana were generated with these samples by

experienced smokers smoking material in this potency range. These

experienced marijuana smokers were reporting that these marijuana

[[Page 20061]]

samples were of “average quality” (Mechoulam, 1973).

    In an early study, Jones (1971) utilized 1 gram of plant material

with a THC concentration of 0.9% (9 mg of THC). Experienced marijuana

smokers were asked to freely smoke marijuana cigarettes for 10 minutes.

The smoking topography of the smokers widely varied and was not

controlled in this set of experiments. Subjects were asked to smoke the

entire cigarette. Subjective state was measured by asking the subjects

to make global estimates of his degree of intoxication on a 0-100

scale. A score of 0 was defined as “sober” and a score of 100 as the

most intoxicated or most “stoned” they had ever been in any social

situation. At the end of the session (about 3 hrs), the subject also

filled out a 272-item symptom checklist (SDEQ: subjective drug effects

questionnaire) which taps some of the more unusual emotional,

perceptual and cognitive effects produced by psychoactive drugs. The

mean potency rating was 61 for the marijuana containing only 9 mg of

THC. There was a tremendous range in the rating made by individual

smokers. Jones concluded that the smokers may obtain intermittent

reinforcement from THC but where much of the behavior and subsequent

response is maintained by “conditioned reinforcers” such as the whole

ritual of lighting up, the associated stimuli of smell, taste, visual

stimuli and so on.

    Manno, Kiplinger, Haine, Bennett, & Forney (1970) asked subjects to

smoke an entire 1 gram cigarette containing 1% THC (10 mg; low

potency). The subjects were told to take 2 to 4 seconds to inhale and

to hold the draw for 30 to 60 seconds. The expired smoke was collected

and analyzed for THC content, as well. During the experiment the

subjects smoked the entire cigarette; in all cases, less than 0.5 mg of

THC remained in the residue of each cigarette. Manno et al. reported

that the quantity of THC or other cannabinols present in a marijuana

cigarette was not a reliable indicator of the amount of cannabinols

that were delivered in the smoke of the cigarette. Controlled smoking

experiments through a manufactured smoking machine demonstrated that

approximately 50% of the \9\-THC originally present in the

cigarette was delivered unchanged in the smoke. Manno et al. concluded

that a dose of approximately 5 mg of \9\-THC was delivered

which was estimated to be an administered dose in the range of 50 to 75

g per kilogram. These low potency marijuana cigarettes

produced significant motor and mental performance measures on the

pursuit meter test, delayed auditory feedback, verbal output, reverse

reading, reverse counting, progressive counting, simple addition,

subtraction, addition +7, subtract +7, and color differentiation. These

low potency cigarettes also produced significant pulse rate increases

and significant increases on a somatic symptoms checklist. Unsolicited

verbal comments from the subjects verified that the subjects were

“high” on these low potency marijuana cigarettes.

    Kiplinger, Manno, Rodda, Forney, Haine, Ease, & Richards (1971)

conducted a randomized block, double-blind study designed to establish

a dose-response analysis of the THC content in marijuana using a

variety of behavioral and subjective effects measures. Marijuana

cigarettes were manufactured to deliver doses of 0, 6.25, 12.5, 25, and

50 g/kg of \9\-THC. Based on an average 70 kg man,

the total delivered doses of THC were 0, 0.43, 0.875, 1.75, and 3.5 mg.

Based on the assumption of a 50% loss of THC from pyrolysis and

sidestream smoke these doses would be equivalent to smoking cigarettes

containing 0, 0.08%, 0.16%, 0.3%, and 0.7% THC containing hemp. The

lower concentrations of THC were used because these doses are found in

the weaker “hemp” or fiber type marijuana commonly grown in the

United States. All doses of THC, including the two lowest doses,

increased the subjective ratings on both the ARCI and Cornell Medical

Indexes, produced heart-rate increases, increased motoric decrements in

pursuit meter, and produced decrements in mental performance using the

delayed auditory feedback test. Most importantly, 80% of subjects

correctly identified the lowest dose (6.25 g/kg; 0.43 mg THC)

as active marijuana. The authors suggested that even lower doses might

have measurable effects. Holtzman (1971) has suggested that one of the

best predictors of a drug’s abuse liability is the identification of

the substance as “drug-like” by experienced drug users. The

identification of the lowest dose of marijuana in the Kiplinger et al.

and the other studies, discussed above, clearly suggests that

industrial “fiber-type” marijuana has abuse potential.

    Many of the studies examining the behavioral effects of marijuana

in animals have chosen to administer THC because of the difficulties in

controlling and administering exact doses within and between subjects

when using pyrolyzed forms of marijuana to animals. Accurate small-

animal smoke delivery systems are not yet available. The lack of water

solubility of \9\-THC has made its administration and

absorption a difficult problem for pharmacologists. Many different

methods for suspending, solubilizing, or emulsifying \9\-THC

have been used. None of these methods are without difficulty and

without influence on absorption and pharmacological activity. The fact

that many methods have been used by various investigators makes

quantitative comparisons difficult.

    \9\-THC is the primary active ingredient of marijuana that

produces the subjective “high” associated with smoking the plant

material and is the chemical basis for cannabis abuse. Studies in

several species of laboratory animals, including rhesus monkeys, rats

and pigeons, have found pharmacological specificity for \9\-

THC at the cannabinoid receptors, and for cannabinoid drugs that bind

with high affinity to brain cannabinoid receptors, and is psychoactive

in humans and animals (Browne and Weissman, 1981; Balster and Prescott,

1992; Compton et al., 1993; Wiley et al., 1995a,b). In general, the

doses that produce its acute therapeutic effects and its cannabimimetic

effects are similar (Devine et al., 1987; Consroe and Sandyk, 1992).

Central Nervous System Effects

    It has been reported that in man, doses above 1 milligram of

\9\-THC absorbed by smoking marijuana are sufficient to cause

a “high” (Agurell et al., 1986). Further, Agurell et al. (1986)

suggested based on mouse data, that a pronounced “high” would be

caused by the presence of as little as 10 micrograms of \9\-

THC in the brain, immediately after smoking a marijuana cigarette.

These conclusions, based on a diverse array of pharmacokinetic studies,

suggest that “fiber-type” marijuana clearly has the capacity to

deposit these levels of THC into the brain of man soon after smoking a

1% THC-containing marijuana cigarette (assuming the typical “joint”

of 1 g, with 10mg THC). \9\-THC exerts its most prominent

effects on the CNS and the cardiovascular system.

    Administration of \9\-THC via smoked cannabis is

associated with decrements in motivation, cognition, judgement, memory,

motor coordination, and alterations in perception (especially time

perception), sensorium, and mood (cf., Jaffe, 1993). Most commonly

\9\-THC produces an increase in well-being and euphoria

accompanied by feelings of relaxation and sleepiness. The consequences

produced by \9\-THC-induced behavioral impairments can greatly

impact the public health and safety, given that individuals may be

[[Page 20062]]

attending school, working, or driving a motor vehicle under the

influence of the drug (i.e., marijuana).

    Preclinical studies show that \9\-THC produces decrements

in short-term memory, as evidenced by disruptions in acquisition and

performance of maze behavior, conditioned emotional responses, and

passive avoidance responses, impairment on the retention in delayed

matching and alternation tests, and increases in resistance to

extinction (Drew and Miller, 1974, Nakamura et al., 1991; Jaarbe and

Mathis, 1992; Lichtman and Martin, 1996). Recent studies in rats found

that these \9\-THC-induced impairments in spatial working

memory were reversible after long abstinence (Nakamura et al., 1991)

and can be blocked by the cannabinoid receptor antagonist SR141716A

(Lichtman and Martin, 1996).

    Memory disturbances are one of the well-documented effects of

“\9\-THC and marijuana on human behavior (Mendelson et al.,

1974; Jaffe, 1993; Hollister, 1986; Chait and Pierri, 1992). Clinical

investigators of \9\-THC and marijuana’s effects in memory

have suggested that the drug produces a deficit in memory for recent

events, and inhibition of the passage of memory from short-term to

long-term storage (Drew and Miller, 1974; Darley 1973a,b).

    Heishman, Huestis, Henningfield, & Cone (1990) demonstrated

cognitive performance decrements in marijuana smokers. Performance

remained impaired on arithmetic and recall tests on the day after smoke

administration. The authors suggested that performance decrements from

smoking two to four marijuana cigarettes may be evident for 24 to 31

hours. These data identify a particular set of performance decrements

which characterize a marijuana-induced abstinence syndrome in man.

Cardiovascular Effects

    In humans, \9\-THC produces an increase in heart rate, an

increase in systolic blood pressure while supine, decreases in blood

pressure while standing, and a marked reddening of the conjunctivae

(cf., Jaffe, 1993). The increase in heart rate is dose-dependent and

its onset and duration varies but lags behind the peak of \9\-

THC levels in the blood.

Respiratory Effects

    Marijuana smoking produces inflammation, edema, and cell injury in

the tracheobronchial mucosa of smokers and may be a risk factor for

lung cancer (Sarafian et al., 1999). Smoke from marijuana has been

shown to stimulate intermediate levels of reactive oxygen species. A

brief, 30-minute exposure to marijuana smoke, regardless of the THC

content, also induced necrotic cell death that increased steadily up to

48 hours after administration. Sarafian et al., concluded that

marijuana smoke containing THC is a potent source of cellular oxidative

stress that could contribute significantly to cell injury and

dysfunction in the lungs of smokers.

    The low incidence of carcinogenicity may be related to the fact

that intoxication from marijuana does not require large amounts of

smoked material. This may be especially true today since marijuana has

been reported to be more potent now than a generation ago and

individuals typically titrate their drug consumption to consistent

levels of intoxication. However, several cases of lung cancer in young

marijuana users with no have been reported (Fung et al., 1999).

    However, a recent study (Zhang et al., 1999, below) has suggested

that marijuana use may dose-dependently interact with mutagenic

sensitivity, cigarette smoking and alcohol use to increase the risk of

head and neck cancer. THC is known to suppress macrophage natural

killer cells and T-lymphocytes and reduce resistance to viral and

bacterial infections. As shown below, Zhu et al., demonstrated that THC

probably interacts with the T-cell cannabinoid CB2 receptor to produce

these effects. As shown in the figure, below, these researchers found

that THC promoted tumor growth in two immunocompetent mice lines. In

two different weakly immunogenic murine lung cancer models,

intermittent administration of THC led to accelerated growth of tumor

implants compared with treatment with placebo alone. The immune

inhibitory cytokines IL-10 and TGF-beta were augmented, while IFN-gamma

was down-regulated at both the tumor site and in the spleens of THC-

treated mice. This has been the first clear demonstration that THC

promotes tumor growth and supports the epidemiological evidence of an

increased risk of cancer among marijuana smokers.

    In a recent comprehensive review of the existing literature base,

Carriot & Sasco (2000) reported that users under the age of 40 years of

age were more susceptible to squamous-cell carcinoma of the upper

aerodigestive tract, particularly of the tongue and larynx, and

possibly the lung. Others tumors being suspected are non-lymphoblastic

acute leukemia and astrocytoma. In head and neck cancer carcinogenicity

was observed for regular (i.e. more than once a day for years) cannabis

smokers. Moreover, cannabis increases the risk of head and neck cancer

in a dose-response manner for frequency and duration of use. THC seems

to have a specific carcinogenic effect different from that of the

pyrolysis products produced by (nicotine) cigarette smoking.

(3) The State of Current Scientific Knowledge Regarding the Drug or

Other Substance

    In general, the petitioner argues that the chemistry, toxicology

and pharmacology of marijuana has been subjected to extensive study and

peer review, and have been well characterized in the scientific

literature. In addition, the discovery of the cannabinoid receptor has

shed new light on the effects of marijuana and its mechanism of action.

    The literature cited by the petitioner (Tashkin et al., 1987, 1988,

1990, 1991, 1993; Barbers et al., 1991; Sherman et al., 1991a, 1991b;

Wu et al., 1992) provide data about the effects of marijuana smoke on

the lungs, which, by the petitioner’s own admission, is inherently

unhealthy. Data show that smoking marijuana is associated with more tar

than cigarettes and holding your breath (a common practice of marijuana

smokers) increases carbon monoxide concentration. His assertion that

Schedule I policy makes promoting safer marijuana smoking habits

impossible has no basis in law (exact citations are found in petition).

    Pulmonary effects of smoked marijuana include bronchodilation after

acute exposure. Chronic bronchitis and pharyngitis are associated with

repeated pulmonary illness. With chronic marijuana smoking, large

airway obstruction and cellular inflammatory abnormalities appear in

bronchial epithelium (Adams and Martin, 1996). Chronic marijuana use is

associated with the same types of health problems as cigarette smoking:

increased frequency of bronchitis, emphysema and asthma. The ability of

alveolar macrophages to inactivate bacteria in the lung is impaired.

Local irritation and narrowing of airways also contribute to problems

in these patients.

    Work by Perez-Reyes et al. (1991) and Agurell et al. (1989)

provides data about the pharmacokinetics of THC from smoked marijuana.

    When marijuana is smoked, THC in the form of an aerosol in the

inhaled smoked is absorbed within seconds and delivered to the brain

rapidly and efficiently. Peak venous blood levels 75-150 ng/ml usually

occur by the end of smoking a cigarette and level of THC

[[Page 20063]]

in the arterial system is probably much higher (Agurell et al., 1986).

    Toxicity by definition is the ability of an agent to produce injury

or cause harm (morbidity/mortality). It is not clear that the effects

of marijuana use are “well-established,” but what is known about the

psychoactive effects, lung effects, endocrine effects etc. would

suggest that smoking marijuana is not benign.

    The cardiovascular effects of smoked or oral marijuana have not

presented any health problems for healthy and relatively young users.

However, marijuana smoking by older patients, particularly those with

some degree of coronary artery disease, is likely to pose greater risks

because of the resulting increased cardiac work, increased

catecholamines, carboxyhemoglobin and postural hypotension (Benzowitz

and Martin, 1996; Hollister, 1988).

    The endocrine system effects include moderate depression of

spermatogenesis and sperm motility and decrease in plasma testosterone

on males. Prolactin, FSH, LH, and GH levels are decreased in females

(Mendelson and Mello, 1984). Relatively little study has been done on

human female endocrine or reproductive function.

    THC and other cannabinoids in marijuana have immunosuppressant

properties producing impaired cell-mediated and humoral immune system

responses. THC and other cannabinoids suppress antibody formation,

cytokine production, leukocyte migration and killer-cell activity

(Adams and Martin, 1996).

    Marijuana may cause membrane perturbations in cells. At the

marijuana conference in July, 1995 sponsored by NIH, NIDA and DHHS, Dr.

Cabral stated that THC effects body functions by accumulating in fatty

tissue. While a receptor-based mechanism of action has been determined,

localized and characterized it is not clear that this necessarily

negates membrane (high fatty acids) effects.

    Mechanisms for marijuana’s psychoactive effects were thought to be

through interactions of the lipid component of cell membranes. The

discovery of the cannabinoid receptor has changed that thinking and it

is now believed that most of the effects of marijuana are mediated

through cannabinoid receptors. Receptors are located in brain areas

concerned with memory, cognition and motor coordination. An endogenous

ligand, anandamide, has been identified but not studied in humans

(Thomas et al. 1996). A specific THC antagonist, SR141716A, produces

intense withdrawal signs and behaviors in rodents that have been

exposed to THC for even a relatively short period of time (Adams and

Martin, 1996). Clinical pharmacology of the antagonist has not been

studied in humans.

    Most of what is known about human pharmacology of smoked marijuana

comes from experiments with plant material containing about 2 percent

THC or less. Very few controlled studies have been done with elderly,

inexperienced or unhealthy users and data suggest that adverse effects

may differ from healthy volunteers (Hollister 1986, 1988).

    Most of what is written about the pharmacological effects of

marijuana is inferred from experiments on pure THC. The amount of

Cannabidiol and other cannabinoids in smoked marijuana could modify the

effects of THC.

    Tolerance to marijuana’s psychoactive effect probably results from

down regulation of cannabinoid receptors which is a form of

desensitization of neuronal cells. In general, tolerance to marijuana’s

effects is often associated with an increased dependence liability.

Data indicate that people escalate the amount of marijuana they smoke

and continue to use marijuana despite negative consequences. These are

classic signs of developing dependence.

    After repeated smoked or oral marijuana doses, marked tolerance is

rapidly acquired to many of marijuana’s effects: cardiovascular,

autoimmune and many subjective effects. After exposure is stopped,

tolerance is lost with similar rapidity (Jones et al., 1981)

    Withdrawal symptoms and signs appearing within hours after

cessation of repeated marijuana use have been reported in clinical

settings (Duffy and Milan, 1996; Mendelson et al., 1984). Typical

symptoms and signs were restlessness, insomnia, irritability,

salivation, diarrhea, increased body temperature and sleep disturbances

(Jones et al., 1981).

    Data on the immune system indicates that marijuana does effect the

body’s ability to resist microbes including bacteria, viruses and fungi

and decreases the body’s antitumor activity. THC effects macrophages,

T-lymphocytes and B-lymphocyts. A THC receptor has been found in the

spleen. These effects may be receptor mediated. In a person with

compromised immune function marijuana could pose a health risk.

    Acute effects of transient anxiety, panic, feelings of depression

and other dysphoric moods have been reported by 17 percent of regular

marijuana users in a large study (Tart, 1971). Whether marijuana can

produce lasting mood disorders or schizophrenia is less clear (IOM,

1982). Chronic marijuana use can be associated with behavior

characterized by apathy and loss of motivation along with impaired

educational performance (Pope and Yurgelun-Todd, 1996).

    DEA has found that since HHS’s last medical and scientific

evaluation on marijuana (1986), there have been a significant number of

new findings relating to THC:

1. Cannabinoid receptors have been identified in the brain and

spleen;

2. The CNS cannabinoid receptor has been cloned;
3. An endogenous arachidonic acid derivative ligand (anandamide)

has been identified;

4. A high density of cannabinoid receptors have been located in the

cerebral cortex, hippocampus, striatum and cerebellum; and

5. An antagonist to the cannabinoid receptor has been developed

    In addition, a significant body of literature has been amassed

regarding the effects of marijuana.

    For example:

1. Studies on the acute and chronic effects of marijuana on the

endocrine system;

2. Effect of marijuana on learning and memory;
3. Effect of marijuana on pregnant females and their offspring

development;

4. Effect on the immune system;
5. Effect on the lungs; and
6. Effects of chronic use with regard to tolerance, dependence and

“amotivational syndrome.”

    While many of the petitioner’s arguments are based on new research

findings, the interpretation of those findings requires clarification.

    As was pointed out by the NIH expert committee on the medical

utility of marijuana, marijuana is not a single drug. It is a variable

and complex mixture of plant parts with a varying mix of biologically

active material. Characterizing the clinical pharmacology is difficult

especially when the plant is smoked or eaten. Some of the inconsistency

or uncertainty in scientific reports describing the clinical

pharmacology of marijuana results from the inherently variable potency

of the plant material. Inadequate control over drug dose together with

the use of research subjects with variable experience in using

marijuana contributes to the uncertainty about what marijuana does or

does not do.

    There are studies in the scientific literature that have evaluated

dose-related subjective and reinforcing effects of Cannabis sativa in

humans. These

[[Page 20064]]

studies have assessed the subjective and reinforcing effects of

cannabis cigarettes containing different potencies of THC and/or which

have manipulated the THC dose by varying the volume of THC smoke

inhaled (Azorlosa et al., 1992; Lukas et al., 1995; Chait et al., 1988;

Chait and Burke, 1994; Kelly et al., 1993; Kipplinger et al, 1971,

Manno et al., 1970).

    Chait et al. (1988) studied the discriminative stimulus effects of

smoked marijuana cigarettes containing THC contents of 0%, 0.9%, 1.4%,

2.7%. Marijuana smokers were trained to discriminate smoked marijuana

from placebo using 4 puff of a 2.7%-THC cigarettes. Subjective ratings

of “high”, mean peak “high” scores, and physiological measures

(i.e., heart rate) were significantly and dose-dependently increased

after smoking the 0.9%, 1.4%, 2.7%. Marijuana cigarettes containing

1.4% THC completely substituted for 2.7%-THC on drug identification

tasks, however, 0.9%-THC did not. The authors found that the onset of

discriminative stimulus effects was within 90 seconds after smoking

began (after the first two puffs). Since the 1.4%-THC cigarette

substituted for 2-puffs of the 2.7%-THC cigarette, the authors estimate

that an inhaled dose of THC as low as 3 mg can produce discriminable

subjective effects.

    Similarly, Lukas et al. (1995) reported that marijuana cigarettes

containing either 1.26% or 2.53% THC produced significant and dose-

dependent increases in level of intoxication and euphoria in male

occasional marijuana smokers. Four of the six subjects that smoked the

1.26%-THC cigarette reported marijuana effects and 75% of these

subjects reported euphoria. All six of the subjects that smoked 2.53%

THC reported marijuana effects and euphoria. Peak levels of self-

reported intoxication occurred at 15 and 30 minutes after smoking and

returned to control levels by 90-105 minutes. There was no difference

between latency to or duration of euphoria after smoking either the

1.26% or 2.53% THC cigarettes. The higher dose-marijuana cigarette

produced a more rapid onset and longer duration of action than the

lower dose marijuana cigarette (1.26% THC). Plasma THC levels peaked 5-

10 minutes after smoking began; the average peak level attained after

the low- and high-dose marijuana cigarette was 36 and 69 ng/ml

respectively.

    In order to determine marijuana dose-effects on subjective and

performance measures over a wide dose range, Azorlosa et al. (1992)

evaluated the effects of 4, 10, or 25 puffs from marijuana cigarettes

containing 1.75 or 3.55% THC in seven male moderate users of marijuana.

Orderly dose-response curves were produced for subjective drug effects,

heart rate, and plasma concentration, as a function of THC content and

number of puffs. After smoking the 1.75% THC cigarette, maximal plasma

THC levels were 57 ng/ml immediately after smoking, 18.3 ng/ml 15

minutes after smoking, 10.3 ng/ml 30 minutes after smoking, and 7.7 ng/

ml 45 minutes after smoking.

    The study also show that subjects could smoke more of the low THC

cigarette to produced effects that were similar to the high THC dose

cigarette (Azorlosa et al., 1992). There were nearly identical THC

levels produced by 10-puff low-THC cigarette (98.6 ng/ml) and 4-puff

high THC cigarette (89.4 ng/ml). Similarly, the subjective effects

ratings, including high, stoned, impaired, confused, clear-headed and

sluggish, produced under the 10 puff low- and high-THC and 25 puff low-

THC conditions did not differ significantly from each other.

    As with most drugs of abuse, higher doses of marijuana are

preferred over lower dose. Although not preferred, these lower doses

still produce cannabimimetic effects. Twelve regular marijuana smokers

participated in a study designed to determine the preference of a low

potency (0.64%-THC) vs. a high potency (1.95%-THC) marijuana cigarette

(Chait and Burke, 1994). The subjects first sampled the marijuana of

two different potencies in one session, then chose which potency and

how much to smoke. During sampling sessions, there were significant

dose-dependent increases in heart rate and subjective effects,

including ratings of peak “high”, strength of drug effects,

stimulated, and drug liking. During choice sessions, the higher dose

marijuana was chosen over the lower dose marijuana on 87.5% of

occasions. Not surprising, there was a significant positive correlation

between the total number of cigarettes smoked and the ratings of

subjective effects, strength of drug effect, drug “liking”, expired

air carbon monoxide, and heart rate increases. The authors state it is

not necessary valid to assume that the preference observed in the

present study for the high-potency marijuana was due to greater CNS

effects from its higher THC content. The present study found that the

low- and high-potency marijuana cigarettes also differ on several

sensory dimensions; the high-potency THC was found to “fresher” and

“hotter”. Other studies found that marijuana cigarettes containing

different THC contents varied in sensory dimensions (cf., Chait et al.,

1988; Nemeth-Coslett et al., 1986).

    As described above in Factors 1 and 2, there are data to show that

the effects of THC are dose-dependent and several studies have found

that low-potency THC is behaviorally active and can produce

cannabimimetic-like subjective and physiological effects. Preclinical

and clinical experimental data demonstrate that marijuana and

9-THC have similar abuse liabilities (i.e., drug

discrimination, self-administration, subjective effects). Both

preclinical and clinical studies show that discontinuation of either

marijuana and 9-THC administration produces a mild

withdrawal syndrome. Most of what is known about human pharmacology of

smoked marijuana comes from experiments with plant material containing

about 2-3% percent THC or less, in cigarette form provided by NIDA

(cf., NIDA, 1996). Very few controlled studies have been done with

elderly, inexperienced or unhealthy users and data suggests that

adverse effects may differ from healthy volunteers (Hollister 1986,

1988).

    Cannabidiol (CBD) does not have psychotomimetic properties and does

not appear to produce a subjective “high” in human subjects (Musty,

1984). This does not mean that CBD does not have CNS effects or that it

does not contribute to the subjective high produced by the

cannabinoids. CBD has been clearly shown to have anti-convulsant

effects as demonstrated by several techniques such as electroshock-

induced seizures, kindled seizures, pentylenetetrazole-induced seizures

(Carlini et al., 1973; Izquierdo & Tannhauser, 1973). The suggestion

that CBD does not have abuse liability is based in part on the findings

that CBD does not produce THC-like discriminative stimulus effects in

animals (Ford, Balster, Dewey, Rosecrans, & Harris, 1984; but see

below). However, these tests were conducted with CBD administered alone

and at only one or two time-points (however, see Jarbe below). The

normal route of administration of THC and CBD in humans is by smoking.

This mode of administration provides a variable proportion of

cannabinoid ratios to the individual subject. As stated above, the

chemistry of marijuana is not just the chemistry of

9-THC , but at a minimum, a combination of

cannabinoids. According to Turner (1980) kinetic interactions have been

reported to occur among the cannabinoids since the early 1970s. Control

studies with varying ratios of cannabinoid administrations and

[[Page 20065]]

complete time-effect functions have still not been conducted.

    Domino, Domino, & Domino (1984) have shown that the rate-of-change

of the subjective high after marijuana administration does not follow

the rate-of-change of plasma or brain THC levels. While plasma THC

function show a sharp ascending limb and exponential decline after

administration, the subjective “high” peaks after the peak in THC and

shows a protracted slow decline. The proportional ratios between the

cannabinoids and their metabolites in inhaled marijuana, acting as

entourage substances, may have emergent properties that cannot be

ascribed to any one component of the complex stimulus administered in

the smoke (Gauvin & Baird, 1999). These cannabinoid ratios may play a

critical role in the initiation, maintenance, and relapse of marijuana

smoking.

    CBD has been clearly shown to have anxiolytic (Guimares et al,

1990, 1994; Musty, 1984; Onaivi, Green, & Martin, 1990; Zuardi et al.,

1982) and antipsychotic (Zuardi et al., 1995; Zuardi, Antunes

Rodrigues, & Cunha, 1991) effects in both animal and man. In the sense

that many studies which have examined the subjective profiles of

marijuana have demonstrated an “anxiety” component to THC and

marijuana use, it should not be surprising that CBD’s anxiolytic

effects block some of these discriminative properties. However, it

should not be concluded from these results that CBD’s anxiolytic

properties do not have or cannot acquire reinforcing efficacy. It has

been suggested that the affective baseline of the drug abuser plays a

critical role in the stimulus properties of drugs (Gauvin, Harland, &

Holloway, 1989). The anxiolytic properties of CBD may serve to diminish

the anxiety states associated with many psychopathological states, thus

effectively functioning as a “negative reinforcer”. As such, CBD may

function to increase the likelihood of its administration by its

ability to remove the negative affective states in anxious patients. A

number of authors have summarized the process by which marijuana

smokers “learn to get high” (cf. Jones, 1971, 1980; Cappell & Pliner,

1974). Karniol et al., (1974) have clearly demonstrated that the co-

administration of CBD with THC actually blocks the anxiety induced by

9-THC, leaving the subjects less tense and

potentiating the reinforcing effects of the THC as demonstrated by the

subjects verbal reports of enjoying the experience even more. Very few

experienced marijuana smokers report symptoms of anxiety (cf Jones,

1971, 1980; Petersen, 1980). The relief of the anxiety and/or

psychotomimetic properties of THC by the co-administration of CBD may

effectively function as a “negative reinforcer”, increasing the

likelihood of continued abuse.

    Other studies have reported that cannabidiol has cannabinoid

properties, including anticonvulsant effects in animal and human models

(Consroe et al., 1981; Carlini et al., 1981; Doyle and Spence, 1995),

hypnotic effects (Monti et al., 1977), and rate-decreasing effects on

operant behavior (Hiltunen et al., 1988). Experiments with cannabidiol

in combination with THC have found that certain behavioral responses

induced by THC (i.e., operant, schedule-controlled responding) were

attenuated by cannabidiol (Borgen and Davis, 1974; Brady and Balster,

1980; Consroe et al., 1977; Dalton et al., 1976; Karniol and Carlini,

1973; Karniol et al., 1974; Welburn et al., 1976; Zuardi and Karniol,

1983; Zuardi et al., 1981, 1982; Hiltunen et al., 1988). However, other

affects produced by THC are augmented or prolonged by the combined

administration of CBD and THC or marijuana extract (Chesher and

Jackson, 1974; Hine et al., 1975a,b; Fernandes et al., 1974; Karniol

and Carlini, 1973; Musty and Sands, 1978; Zuardi and Karniol, 1983;

Zuardi et al., 1984). Still other studies did not report any behavioral

interaction between the CBD and THC (Bird et al., 1980; Browne and

Weissman, 1981; Hollister and Gillespie, 1975; Jarbe and Henricksson,

1974; Jarbe et al., 1977; Mechoulam et al., 1970; Sanders et al., 1979;

Ten Ham and DeLong, 1975).

    A study to characterize the interaction between CBD and THC was

conducted using preclinical drug discrimination procedures. Rats and

pigeons trained to discriminate the presence or absence of THC, and

tested with CBD administered alone and in combinations with THC

(Hiltunen and Jarbe, 1986). Specifically, in rats trained to

discriminate 3.0 mg/kg, i.p. THC, CBD (30.0 mg/kg) was administered

alone and in combination with THC (0.3 and 1.0 mg/kg, i.p.). In pigeons

trained to discriminate 0.56 mg/kg, i.m. THC, CBD (17.5 mg/kg) was

administered alone and in combination with THC (0.1, 0.3, and 0.56 mg/

kg, i.m.). CBD prolonged the discriminative stimulus effects of THC in

rats, but did not change the time-effect curve for THC in pigeons. In

pigeons, the administration of CBD did not produce any differential

effect under a fixed ratio schedule of reinforcement (Hiltunen and

Jarbe, 1986).

    These data suggest that CBD may somehow augment or prolong the

actions of THC in rats and had no effect in pigeons. In the present

study, the CBD/THC ratios ranged from 30:1 to 100:1 in rats and

enhanced the stimulus effects of THC. However, similar CBD/THC ratios

in pigeons (31:1, 58:1 and 175:1) did not result in any changes to

THC’s discriminative stimulus or response rate effects (Hiltunen and

Jarbe, 1986).

    In conclusion, although cannabidiol does contribute to the other

effects of cannabis, it appears to lack cannabimimetic properties. In

addition, there does not appear to be a scientific consensus that

cannabidiol pharmacologically antagonizes, in a classic sense, the

effects of THC. Certain functional blockades have been demonstrated. As

presented in the scientific literature cited above, the ability of

cannabidiol to modify the effects of THC may be specific to only some

effects of THC. Most importantly, CBD appears to potentiate the

euphorigenic and reinforcing effects of THC which suggests that the

interaction between THC and CBD is synergistic and may actually

contribute to the abuse of marijuana.

(4) Its History and Current Pattern of Abuse

    The federal databases documenting the actual abuse of marijuana are

distributed and maintained by the HHS, therefore, we acknowledge and

concur with HHS’s review of this factor analysis.

(5) The Scope, Duration, and Significance of Abuse

    The basis of the petition to remove marijuana from Schedules I and

II is not based on data required by 21 U.S.C. 811 (c) (i.e., the scope,

duration, and significance of use of the substances).

    The petitioner seems to assume that the concept, use of an illegal

substance is abuse of that substance, is a concept which is universally

held to the exclusion of any other definition of abuse of a substance.

While this concept is valid in general terms because marijuana is not a

legitimately marketed product therefore it has no legitimate use,

holding that all adhere to this definition of abuse denigrates the

intellectual capacity of all researchers who investigate the topic. The

petitioner neglects to recognize the efforts of the DHHS and many

groups which expend a great deal of time and money in research efforts

directed toward developing and implementing drug-abuse prevention

programs. The petitioner also rejects the notion that there are

individuals who abuse marijuana even though the National Household

Survey, to which the

[[Page 20066]]

petitioner refers, would indicate that is the case.

    It has not been established that marijuana is effective in treating

any medical condition. (NIH Workshop on the Medical Utility of

Marijuana, 1997) At this time, there is no body of knowledge to which a

physician can turn to learn which medical condition in which patient

will be ameliorated at which dosage schedule of smoked marijuana nor

can he/she determine in which patient the benefits will exceed the

risks associated with such treatment. The petitioner, therefore, is

advocating that individuals become their own physicians, a notion that

even primitive man found unsatisfactory.

    There is nothing absolute in the placement of a substance into a

particular CSA schedule. The placement of a substance in a CSA schedule

is the government’s mechanism for seeing that the availability of

certain psychoactive substances is limited to the industrial,

scientific and medical needs which are accepted as being legitimate.

The placement of a substance into Schedule I does not preclude research

of that substance, nor does it preclude development of a marketable

product. The National Institute on Drug Abuse, an element of the

Department of Health and Human Services, convened a conference in 1995

and with NIDA’s parent organization, the National Institutes of Health,

assembled an ad hoc group of experts in 1997 to address issues related

to the use, abuse, and medical utility of marijuana. With regard to the

medical utility of marijuana, the experts concluded that the scientific

process should be allowed to evaluate the potential therapeutic effects

of marijuana for certain disorders, dissociated from the societal

debate over the potential harmful effects of nonmedical marijuana use.

All decisions on the ultimate usefulness of a medical intervention are

based on a benefit/risk calculation, and marijuana should be no

exception to this generally accepted principle.

    The cause and effect relationship which the petitioner poses is

neither substantiated nor relevant. Estimates are useful when

attempting to allocate resources but they are not necessary for

effective eradication of marijuana. Each year, millions of plants are

destroyed before their product reaches the market. In addition, federal

law enforcement activities result in the seizure of another million or

more pounds of product annually.

    As reviewed by Gledhill, Lee, Strote, & Wechsler (2000), rates of

illicit drug use, especially marijuana, have risen uniformly among the

youth in the United States in the past decade and remained steady at

the end of the 1990s despite efforts to reduce prevalence. Between 1991

and 1997, rates of past 30-day marijuana use had more than doubled

among U.S. 10th grade secondary school students and more than tripled

among seniors, after a decade of decline. Between 1997 and 1999, rates

of marijuana use among secondary school students declined for the first

time in the 1990s mainly among the older students (16-17 yrs old).

    Disturbing are the findings that marijuana use is steadily

increasing among 8th, 10th and 12th graders at all prevalence levels.

According to the 1996 survey results from the Monitoring the Future

Study, 45% of seniors and 35% of 10th graders claimed to have used

marijuana at least once. Among eighth graders, annual prevalence rates

more nearly tripled 1992 to 1996. Accompanying the increased use of

marijuana among High School seniors is a decreasing perceived risk or

harm of marijuana use (Johnston et al., 1996). In reality, the harm

associated with the abuse of marijuana is increasing; the marijuana

emergency room and treatment admission rates continue to increase in

recent years.

    Gledhill-Hoyt, Lee, Strote, & Wechsler (2000) examined rates and

patterns of marijuana use among different types of students and

colleges in 1999, and changes in use since 1993. 15,403 students in

1993, 14,724 students in 1997, and 14,138 students in 1999 were

assessed. The prevalence of past 30-day and annual marijuana use

increased in nearly all student demographic subgroups, and at all types

of colleges. Nine out of 10 students (91%) who used marijuana in the

past 30 days had used other illicit drugs, smoked cigarettes, and/or

engaged in binge drinking. Twenty-nine percent of past 30-day marijuana

users first used marijuana and 34% began to use marijuana regularly at

or after the age of 18, when most were in college.

    Coffey, Lynskey, Wolfe, & Patton (2000) examined predictors of

cannabis use initiation, continuity and progression to daily use in

adolescents. Over 2,000 students were examined. Peer cannabis use,

daily smoking, alcohol use, antisocial behavior and high rates of

school-level cannabis use were associated with middle-school cannabis

use and independently predicted high-school uptake. Cannabis use

persisted into high-school use in 80% of all middle-school users.

Middle-school use independently predicted incidents in high-school

daily use in males, while high-dose alcohol use and antisocial behavior

predicted incidence of daily use in high school females. The authors

also found that cigarette smoking was an important predictor of both

initiation and persisting cannabis use.

    Farrelly et al., (2001) reviewed the NHSDA from 1990 through 1996

and compared those statistics with State law enforcement policies and

prices that affect marijuana use in the general public. These authors

found evidence that both higher fines for marijuana possession and

increased probability of arrest decreased the probability that a young

adult will use marijuana. These new data refute the petitioner’s

suggestion that legal control of marijuana does not have a dampening

effect on its use.

(6) What, if any, Risks are There to Public Health

    There are human data demonstrating that marijuana and

9-THC produce an increase in heart rate, an

increase in systolic blood pressure while supine, and decreases in

blood pressure while standing (cf., Jaffe, 1993). The increase in heart

rate is dose-dependent and its onset and duration correlate with levels

of 9-THC in the blood.

    When DEA evaluates a drug for control or rescheduling, the question

of whether the substance creates dangers to the public health, in

addition to, or because of, its abuse potential must be considered. A

drug substances’ risk to the public health manifests itself in many

ways. Abuse of a substance may affect the physical and/or psychological

functioning of an individual abuser. In addition, it may have

disruptive effects on the abuser’s family, friends, work environment,

and society in general. Abuse of certain substances leads to a number

of antisocial behaviors, including violent behavior, endangering

others, criminal activity, and driving while intoxicated. Data examined

under this specific factor of the CSA ranges from preclinical toxicity

to postmarketing adverse reactions in humans. DEA reviews data from

many sources, including forensic laboratory analyses, crime

laboratories, medical examiners, poison control centers, substance

abuse treatment centers, and the scientific and medical literature.

    Adverse effects associated with marijuana and THC as determined by

clinical trials, FDA adverse drug effects and World Health Organization

data, are described elsewhere (cf., Chait and Zacny, 1988; Chait and

Zacny, 1992; Cone et al., 1988; and Pertwee, 1991). A recent press

release from the Substance Abuse and Mental Health Service

Administration reported that adolescents, age 12 to 17, who use

[[Page 20067]]

marijuana weekly are nine times more likely than non-users to

experiment with illegal drugs or alcohol; six times more likely to run

away from home; five times more likely to steal; nearly four times more

likely to engage in violence; and three times more likely to have

thoughts about committing suicide. It was also reported that

adolescents also associated social withdrawal, physical complaints,

anxiety, and depression, attention problems, and thoughts of suicide

with past-year marijuana use (SAMHSA, 1999). Budney, Novy, & Hughes

(1999) have recently examined the withdrawal symptomology in chronic

marijuana users seeking treatment for their dependence. The majority of

the subjects (85%) reported that they had experienced symptoms of at

least moderate severity and 47% experienced greater than four symptoms

rated as severe. The most reported mood symptoms associated with the

withdrawal state were irritability, nervousness, depression, and anger.

Some of the behavioral characteristics of the marijuana withdrawal

syndrome were craving, restlessness, sleep disruptions, strange dreams,

changes in appetite, and violent outbursts. These data clearly support

the validity and clinical significance of a marijuana withdrawal

syndrome in man.

Toxic Effects of Marijuana and THC

    Although a median lethal dose (LD50) of THC has not been

established in humans, it has been found in laboratory animals

(Phillips et al., 1971). In mice, the LD50 for THC was

481.9, 454.9 and 28.6 mg/kg after oral, intraperitoneal, and

intravenous routes of administration. In rats, the LD50 for

THC (extracted from marijuana) was 666.0, 372.9 and 42.5 mg/kg after

oral, intraperitoneal, and intravenous routes of administration.

Another study examined the toxicity of THC in rats, dogs and monkeys

(Thompson et al., 1972). Similarly this study found that in rats, the

LD50 for THC was 1140.0, 400.0 and 20.0 mg/kg after oral,

intraperitoneal, and intravenous routes of administration. There was no

LD50 attained in monkeys and dogs by the oral route. Over

3000 mg/kg of THC was administered without lethality to dogs and

monkeys. A dose of about 1000 mg/kg was the lowest dose that caused

death in any animal. Behavioral changes in the survivors included

sedation, huddled postures, muscle tremors, hypersensitivity to sound

and immobility.

    The cause of death in the rats and mice after oral THC was profound

depression leading to dyspnea, prostration, weight loss, loss of

righting reflex, ataxia, and severe decreases in body temperature

leading to cessation of respiration from 10 to 40 hours after a single

oral dose (Thompson et al., 1972). No consistent pathologic changes

were observed in any organs. The cause of death in dogs or monkeys

(when it rarely occurred) did not appear to be via the same mechanism

as in the rats.

    In humans, the estimated lethal dose of intravenous dronabinol

[(-)-\9\-THC] is 30 mg/kg (2100 mg/70 kg). In antiemetic

studies, significant CNS symptoms were observed following oral doses of

0.4 mg/kg (28 mg/70 kg) (PDR, 1997). Signs and symptoms of mild

dronabinol intoxication include drowsiness, euphoria, heightened

sensory awareness, altered time perception, reddened conjunctiva, dry

mouth and tachycardia. Following moderate dronabinol intoxication

patients may experience memory impairment, depersonalization, mood

alterations, urinary retention, and reduced bowel motility. Signs and

symptoms of severe dronabinol intoxication include decreased motor

coordination, lethargy, slurred speech, and postural hypotension.

Dronabinol may produce panic reactions in apprehensive patients or

seizures in those with an existing seizure disorder (PDR, 1997).

    Thus, large doses of THC ingested by mouth were not often

associated with toxicity in dogs, nonhuman primates and humans.

However, it did produce fatalities in rodents as a result of profound

CNS depression. Thus, the evidence from studies in laboratory animals

and human case reports indicates that the lethal dose of THC is quite

large. The adverse effects associated with THC use are generally

extensions of the CNS effects of the drug and are similar to those

reported after administration of marijuana (cf., Chait and Zacny, 1988;

Chait and Zacny, 1992; Cone et al., 1988; and Pertwee, 1991).

Health and Safety Risks of \9\-THC Use

    The recent Institute of Medicine report on the scientific basis for

the medicinal use of cannabinoid products stated the following:

    Not surprisingly, most users of other illicit drugs have used

marijuana first. In fact, most drug users begin with alcohol and

nicotine before marijuana–usually before they are of legal age. In

the sense that marijuana use typically precedes rather than follows

initiation of other illicit drug use, it is indeed a “gateway”

drug (Institute of Medicine Report 1999, p. ES.7).

    Golub and Johnson (1994) examined the developmental pathway

followed by a sample of persons who became serious drug abusers. Of the

837 persons sampled 84% had onset to more serious drugs by the time of

the interviews. Most of the sample reported having used marijuana

(91%). Two-thirds of the drug abusers reported having used marijuana

prior to onset to more serious drugs and an additional 19% reported

having onset to marijuana and more serious drugs in the same year.

These data strongly suggest that marijuana does plan an important role

on the pathway to more serious drugs use. Further, the proportion who

onset to marijuana before or in the same year as more serious drugs was

reported to have increased substantially with time from a low of 78%

for persons born from 1928 to 1952 to 95% for the most recent birth

cohort of the study (1968-1973). These findings further suggest that

marijuana’s role as a gateway to more serious substance sue has become

more pronounced over time.

    Ferguson & Horwood (2000) have examined the relationship between

cannabis use in adolescence and the onset of other illicit drug use.

Data were gathered over the course of a 21 year longitudinal study of a

birth cohort of 1,265 children. By the age of 21, just over a quarter

of this cohort reported using various forms of illicit drugs on at

least one occasion. In agreement with the predictions of a “stage-

theory” of the “gateway hypothesis” there was strong evidence of a

temporal sequence in which the use of cannabis preceded the onset of

the use of other illicit drugs. Of those reporting the use of illicit

drugs, all but three (99%) had used cannabis prior to the use of other

illicit drugs. However, the converse was not true and the majority

(63%) of those using cannabis did not progress to the use of other

forms of illicit drugs. In addition, to these findings there was a

strong dose-response relationship between the extent of cannabis use

and the onset of illicit drug use. The analysis suggested that those

using cannabis in any given year on at least 50 occasions had hazards

of using other illicit drugs that were over 140 times higher than those

who did not use in the year. Furthermore, hazards of the onset of other

illicit drug use increased steadily with increasing cannabis use. The

very strong gradient in risk reflected the facts that: (1) Among non-

users of cannabis the use of other forms of illicit drugs was almost

non-existent and (2) among regular users of cannabis the use of other

illicit drugs was common. To address the issue of “confounding

factors”, the associations between cannabis use and the onset of

illicit drug use were adjusted for a series of

[[Page 20068]]

prospectively measured confounding factors that included measures of

social disadvantage, family functioning, parental adjustment,

individual characteristics, attitudes to drug use and early adolescent

behavior. After adjustments for these factors, there was still evidence

of strong dose-response relationships between the extent of cannabis

use in a given year and the onset of illicit drug use–the hazards of

the onset of illicit drug use was 100 times those of non-users.

    Critics of the “gateway theory” point to the presence of other

confounding factors and processes that encourage both cannabis use and

other forms of illicit drug use. Despite these factors, the Ferguson &

Horwood (2000) study provide a compelling set of results that support

the hypothesis that cannabis use may encourage other forms of illicit

drug use, including the following:

1. Temporal sequence: There was clear evidence that the use of

cannabis almost invariably preceded the onset of other forms of

illicit drug use.

2. Dose-Response: There was clear evidence of a very strong and

consistent dose-response relationship in which increasing cannabis

use was associated with increasing risks of the onset of illicit

drug use.

3. Resilience to control for confounding: Even following control

for a range of prospectively measured social, family and individual

factors, strong and consistent associations remained between

cannabis use and the onset of other forms of illicit drug use. And,

4. Specificity of associations: The association could not be

explained as reflecting a more general process of transition to

adolescent deviant behavior since even after control for

contemporaneously assessed measures of juvenile offending, alcohol

use, cigarette smoking, unemployment and related measures, strong

and consistent relationships between cannabis use and the onset of

other forms of illicit drugs remained.

    A suggested view of the “gateway hypothesis” states that the use

of cannabis may be associated with increasing risks of other forms of

illicit drug use, with this relationship being mediated by affiliations

with deviant peers and other non-observed processes that may encourage

those who use cannabis (and particularly heavy users) to experiment

with, and use, other illicit drugs.

    While marijuana is clearly not the only gateway to the use of other

illicit drugs it is one of the three most typical drugs in the

adolescent’s armamentarium. The increased avenues to imported and

“home-grown” marijuana which contain behaviorally-active doses of THC

and CBD pose a serious threat to the health and well-being of this

dimension of society.

    Taylor et al. (2000) evaluated the relationship between cannabis

dependence and respiratory symptoms and lung function in young adults,

21 years of age, while controlling for the effects of cigarette

smoking. The researchers found significant respiratory symptoms and

changes in spirometry occur in cannabis-dependent individuals at age 21

years, even though the cannabis smoking history is of relatively short

duration. The likelihood of reporting a broad range of respiratory

symptoms was significantly increased in those who were either cannabis-

dependent or smoked tobacco or both compared to non-smokers. The

symptoms most frequently and significantly associated with cannabis

dependence were early morning sputum production (144% greater

prevalence than non-smokers). Overall, respiratory symptoms in study

members who met strict criteria for cannabis dependence were comparable

to those of tobacco smokers consuming 1-10 cigarettes daily. In

subjects who were both tobacco users and were cannabis-dependent, some

effects seem to be additive, notably early morning sputum production,

which occurred 8 times more frequently than non-smokers.

    One of the greatest concerns to society regarding \9\-THC

is the behavioral toxicity produced by the drug. \9\-THC

intoxication is associated with impairments in memory, motor

coordination, cognition, judgement, motivation, sensation, perception

and mood (cf., Jaffe, 1993). The consequences produced by \9\-

THC-induced behavioral impairments can greatly impact the individual

and society in general. These impairments result in occupational,

household, or airplane, train, truck, bus or automobile accidents,

given that individuals may be attending school, working, or operating a

motor vehicle under the influence of the drug. In the most general

sense, impaired driving can be seen as a failure to exercise the

expected degree of prudence or control necessary to ensure road safety.

The operations of a motor vehicle are clearly a skilled performance

that requires controlled and flexible use of a person’s intellectual

and perceptual resources. Cannabis interferes with resource allocations

in both cognitive and attentional tasks.

    In 1999, Ehrenreich et al., examined the detrimental effects of

chronic interference by cannabis with the endogenous cannabinoid

systems during peripubertal development in humans. As an index of

cannabinoid action, visual scanning and other attentional factors were

examined in 99 individuals who exclusively used cannabis. Early-onset

cannabis use (onset before the age of 16) showed significant

impairments in attention in adulthood. These persistent attentional

deficits may interact with the activities of daily living, such as

operating an automobile.

    Kurzthaler et al., (1999) examined the effects of cannabis on a

cognitive test battery and driving performance skills. The demonstrated

significant impairments in the verbal memory and the trail making tests

in this study reflect parallel compromises in associative control that

is acknowledged as a cognitive process inherent in memory function

immediately after smoking cannabis. Applied to the question of driving

ability, the authors suggest that the missing functions would signify

that a driver under acute cannabis influences would not be able to use

acquired knowledge from earlier experiences adequately to ensure road

safety.

    Recently, the National Highway Traffic Safety Administration

(NHTSA; 1998, 1999, 2000) conducted a study with the Institute for

Human Psychopharmacology at Maastricht University in The Netherlands.

Low dose and high dose THC administered alone, and with alcohol were

examined in two on-road driving situations: (1) The Road Tracking Test,

measuring a driver’s ability to maintain a constant speed of 62 mph and

a steady lateral position between the boundaries of the right traffic

lane; and (2) the Car Following Test, measuring a drivers’ reaction

times and ability to maintain distance between vehicles while driving

164 ft. behind a vehicle that executed a series of alternating

accelerations and decelerations. Both levels of THC alone, and alcohol

alone, significantly impaired performances on BOTH road tests compared

with baseline. Alcohol and the high dose of THC produced 36% decrements

in reaction time; because the test vehicles were traveling at 59 mph,

the delayed reaction times meant that the vehicle traveled, on average,

an additional 139 feet beyond the point where the subjects began to

decelerate. Even the lower dose of THC by itself retarded reaction

times by 0.9 seconds. The NHTSA concluded that even in low to moderate

doses, marijuana impairs driving performance.

    In a related analysis, Yesavage, Leirer, Denari, & Hollister (1985)

examined the acute and delayed effects of smoking one marijuana

cigarette containing 1.9% THC (19 mg of THC) on aircraft pilot

performance. Ten private pilot licensed subjects were trained in a

flight simulator prior to marijuana exposure. Flight simulator

performance was

[[Page 20069]]

measured by the number of aileron (lateral control), elevator (vertical

control) and throttle changes; the size of these control changes; the

distance off the center of the runway on landing; and the average

lateral and vertical deviation from an ideal glideslope and center line

over the final mile of the approach. Compared to baseline performance,

significant differences occurred in all variables at 1 and 4 hours

after smoking, except for the numbers of throttle and elevator changes

at 4 hours. Most importantly, at 24 hours after a single marijuana

cigarette, there were significant impairments in the number and size of

aileron (lateral control) changes, size of elevator changes, distance

off-center on landing, and vertical and lateral deviations on approach

to landing. Interestingly, despite these performance deficits, the

pilots reported no significant subjective awareness of their

impairments at 24 hours. It is noteworthy that a fatal crash in which a

pilot had a positive THC screen involved similar landing misjudgments.

    In addition to causing unsafe conditions, marijuana use results in

decreased performance and lost productivity in the workplace, including

injuries, absenteeism, and increased health care costs. A NIDA report

on drugs in the workplace summarized the prevalence of marijuana use in

the workplace and its impact on society. This report found that in

1989, one in nine working people (11%) reported current use of

marijuana (Gust and Walsh, 1989). Recent DAWN data and other surveys

indicate that marijuana use is increasing, especially among younger and

working age individuals.

    Bray, Zarkin, Ringwalt, & Qi (2000) estimated the impact of age of

dropout on the relationship between marijuana use and high school

dropouts using four longitudinal surveys from students in the

Southeastern U.S. public school system. Their results suggested that

marijuana initiation was positively related to high school dropout.

Although the magnitude and the significance of the relationship varied

with age of dropout and the other substances used, the overall effect

represented an odds-ratio of approximately 2.3. These data suggest that

an individual is approximately 2.3 times more likely to drop out of

school than an individual who has not initiated marijuana use.

    When DEA evaluates a drug for control or rescheduling, whether the

substance creates dangers to the public health, in addition to or

because of its abuse potential, must be considered. The risk to the

public health of a substance may manifest itself in many ways. Abuse of

a substance may affect the physical and/or psychological functioning of

an individual abuser, it may have disruptive effects on the abuser’s

family, friends, work environment, and society in general. Abuse of

certain substances leads to a number of antisocial behaviors, including

violent behavior, endangering others, criminal activity, and driving

while intoxicated. Data examined under this factor ranges from

preclinical toxicity to postmarketing adverse reactions in humans. DEA

reviews data from many sources, including forensic laboratory analyses,

crime laboratories, medical examiners, poison control centers,

substance abuse treatment centers, and the scientific and medical

literature.

    In its official report titled “Marijuana and Medicine: Assessing

the Science Base”, the Institute of Medicine highlighted a number of

risks to the public health as a result of cannabis consumption:

    (1) Cognitive impairments associated with acutely administered

marijuana limit the activities that people would be able to do

safely or productively. For example, no one under the influence of

marijuana or THC should drive a vehicle or operate potentially

dangerous equipment (Page 107).

    (2) The most compelling concerns regarding marijuana smoking in

HIV/AIDS patients are the possible effects of marijuana on immunity.

Reports of opportunistic fungal and bacterial pneumonia in AIDS

patients who used marijuana suggest that marijuana smoking either

suppresses the immune system or exposes patients to an added burden

of pathogens. In summary, patients with pre-existing immune deficits

due to AIDS should be expected to be vulnerable to serious harm

caused by smoking marijuana. The relative contribution of marijuana

smoke versus THC or other cannabinoids is not known. (Page 116-117)

    (3) DNA alterations are known to be early events in the

development of cancer, and have been observed in the lymphocytes of

pregnant marijuana smokers and in those of their newborns. This is

an important study because the investigators were careful to exclude

tobacco smokers; a problem in previous studies that cited mutagenic

effects of marijuana smoke. (Page 118-119)

    (4) * * * factors influence the safety of marijuana or

cannabinoid drugs for medical use: the delivery system, the use of

plant material, and the side effects of cannabinoid drugs. (1)

Smoking marijuana is clearly harmful, especially in people with

chronic conditions, and is not an ideal drug delivery system. (2)

Plants are of uncertain composition, which renders their effects

equally uncertain, so they constitute an undesirable medication.

(Page 127)

(7) Its Psychic or Physiological Dependence Liability

    The “dopaminergic hypothesis of drug abuse” is not the only

explanation for the neurochemical actions of drugs. The nucleus

accumbens/ventral striatum areas of the brain, typically referred to as

simply the Nucleus Accumbens (NAc), represents a critical site for

mediating the rewarding or hedonic properties of several classes of

abused drugs, including alcohol, opioids, and psychomotor stimulants

(Gardner & Vorel, 1998; Koob, 1992; Koob et al., 1998; Wise, 1996; Wise

& Bozarth, 1987). It is generally appreciated that all of these drugs

augment extracellular dopamine levels in the NAc and that this action

contributes to their rewarding properties. However, recent evidence

also suggests that many drugs of abuse have dopamine-independent

interactions with Nac neuronal activity (Carlezon & Wise, 1996; Chieng

& Williams, 1998; Koob, 1992; Martin et al., 1997; Yuan et al., 1992).

Recent studies conducted at the Cellular Neurobiology Branch of the

NIDA by Hoffman & Lupica (2001) concluded that THC modulates NAc

glutamatergic functioning of dopamine. These authors suggested that

increases in Nac dopamine levels may be a useful neurochemical index of

drug reward but do not fully account for the complex processing of fast

synaptic activity by this neuromodulator in the Nac. Moreover, because

both glutamatergic and GABAergic inputs to medium spiny neurons are

directly inhibited by dopamine, as well as by drugs of abuse. It is

likely that these effects contribute to the abuse liability of

marijuana.

    In addition, the petitioner’s global statements about the role of

dopamine, the reinforcing effects of marijuana and other drugs, and the

predictive validity of animal self-administration studies with

marijuana and abuse potential in humans are not supported by the

scientific literature. For example:

    (1) There are drugs that do not function through dopaminergic

systems that are self-administered by animals and humans (i.e.,

barbiturates, benzodiazepines, PCP).

    (2) There are drugs that are readily self-administered by animals

that are not abused by man (antihistamines)

    (3) There are drugs that are abused by humans that are not readily

self-administered by animals (hallucinogens and hallucinogenic

phenethylamines, nicotine, caffeine).

    (4) There are drugs that have no effect on dopamine that are self-

administered

[[Page 20070]]

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

Physical Dependence in Animals

    Abrupt withdrawal from 9-THC can produce a mild

spontaneous withdrawal syndrome in animals, including increased motor

activity and grooming in rats, decreased seizure threshold in mice and

increased aggressiveness, irritability and altered operant performance

in rhesus monkeys (cf., Pertwee, 1991). The failure to observe profound

withdrawal signs following abrupt discontinuation of

9-THC may be due to (1) its long half-life in

plasma and (2) slowly waning levels of 9-THC and

its metabolites that continue to permit receptor adaptation.

    Recently the discovery of a cannabinoid receptor antagonist

demonstrates that a profound precipitated withdrawal syndrome can be

produced in 9-THC tolerant animals after twice

daily injections (Tsou et al., 1995) or continuous infusion (Aceto et

al., 1995, 1996). In rats continuously infused with low doses

9-THC for four days, the cannabinoid antagonist

precipitated a behavioral withdrawal syndrome, including scratching,

face rubbing, licking, wet dog shakes, arched back and ptosis (Aceto et

al., 1996). This chronic low dose regimen consisted of 0.5, 1, 2, 4 mg/

kg/day 9-THC on days 1 through 4; 5 and 25-fold

higher 9-THC doses were used for the medium and

high dose regimens, respectively. The precipitated withdrawal syndrome

was dose-dependently more severe in the medium and high THC dose

groups.

Physical Dependence in Humans

    Signs of withdrawal have been demonstrated after studies with

9-THC. Although the intensity of the withdrawal

syndrome is related to the daily dose and frequency of administration,

in general, the signs of 9-THC withdrawal have been

relatively mild (cf., Pertwee, 1991). This withdrawal syndrome has been

compared to that of a short-term, low dose treatment with an opioid or

ethanol, and includes changes in mood, sleep, heart rate body

temperature, and appetite. Other signs such as irritability,

restlessness, tremor mild nausea, hot flashes and sweating have also

been noted (cf., Jones, 1983).

    A withdrawal syndrome was reported after the discontinuation of

oral THC in volunteers receiving dronabinol dosages of 210 mg/day for

12 to 16 consecutive days (PDR, 1997). This was 42-times the

recommended dose of 2.5 mg, b.i.d. Within 12 hours after

discontinuation, these volunteers manifested withdrawal symptoms such

as irritability, insomnia, and restlessness. By approximately 24 hours

after THC discontinuation, there was an intensification of withdrawal

symptoms to include “hot flashes”, sweating, rhinorrhea, loose

stools, hiccoughs, and anorexia. These withdrawal symptoms gradually

dissipated over the next 48 hours. EEG changes consistent with the

effects of drug withdrawal (hyperexcitation) were recorded in patients

after abrupt challenge. Patients also complained of disturbed sleep for

several weeks after discontinuation of high doses of dronabinol. The

intensity of the cannabinoid withdrawal syndrome is related by the

chronic dose and by the frequency of chronic administration. There is

also evidence that the cannabinoid withdrawal symptoms can be reversed

by the administration of marijuana and 9-THC, or by

treatment with a barbiturate (hexobarbital) or ethanol (Pertwee, 1991).

    An acute withdrawal syndrome or “hangover” has been reported by

Chait, Fischman, & Schuster (1985) developing approximately 9 hours

after smoking a 1 g marijuana cigarette containing 2.9% THC. Five of

twelve subjects reported themselves as “dopey and hung over” the

morning after smoking the single cigarette. In a 10 second and 30

second time-production task significant marijuana hangover effects were

found. The effect on the time production task is of interest since the

effect obtained the morning after smoking marijuana was opposite to

that observed acutely after smoking marijuana. These data may suggest

an opponent compensatory rebound which may underlie the development of

tolerance over periods of chronic marijuana exposure. Scores on the

benzedrine-group (BG) scale, a stimulant scale of the Addiction

Research Center Inventory (ARCI) consisting mainly of terms relating to

intellectual efficiency and energy, were significantly higher the

morning after marijuana smoking, as well. Chait, Fischman, & Schuster

also reported increases on the amphetamine (A) scale of the ARCI, a

measure of the dose-related effects of d-amphetamine. Cousens &

DiMascio (1973) have previously reported a similar “hangover” and

“speed of thought alterations” in subjects the morning after they had

received a 30 mg oral dose of 9-THC. Like the

“hangover” associated with high dose ethyl alcohol consumption, the

hangover from marijuana may be qualitatively identical to, and differ

only on an intensity dimension from, the withdrawal syndrome produced

from chronic consumption (cf. Gauvin, Cheng, Holloway, 1993).

    As described above, Haney et al. have recently described abstinence

symptoms of an acute withdrawal syndrome following high (30 mg q.i.d.)

and low (20 mg q.i.d) dose administrations of oral THC (Haney et al.,

1999a) and following 5 puffs of high (3.1%) and low (1.8%) THC-

containing smoked marijuana cigarettes (Haney et al., 1999b). Both of

these studies have delineated a withdrawal syndrome from concentrations

of THC significantly lower than those reported in any other previous

study and, for the first time, clearly identified a marijuana

withdrawal syndrome detected at low levels of THC exposure that do not

produce tolerance. These data suggest that dependence on THC may in

fact be an important consequence of repeated, daily exposure to

cannabinoids and that daily marijuana use may be maintained, at least

in part, by the alleviation of abstinence symptoms.

    As stated above, Budney, Novy, & Hughes (1999) have recently

examined the withdrawal symptomology in chronic marijuana users seeking

treatment for their dependence. The majority of the subjects (85%)

reported that they had experienced symptoms of at least moderate

severity and 47% experienced greater than four symptoms rated as

severe. The most reported mood symptoms associated with the withdrawal

state were irritability, nervousness, depression, and anger. Some of

the behavioral characteristics of the marijuana withdrawal syndrome

were craving, restlessness, sleep disruptions, strange dreams, changes

in appetite, and violent outbursts. These data clearly support the

validity and clinical significance of a marijuana withdrawal syndrome

in man. Large-scale population studies have also reported significant

rates of cannabis dependence (Kessler et al., 1994; Farrell et al.,

1998), particularly in prison and homeless populations. Similar reports

of cannabis dependence in withdrawal in other populations have been

previously discussed (above; Crowley et al. (1998); Kouri & Pope

(2000)).

Psychological Dependence in Humans

    In addition to the physical dependence produced by abrupt

withdrawal from 9-THC, psychological dependence on

9-THC can also be demonstrated. Case reports and

clinical studies show that frequency of 9-THC use

(most often as marijuana) escalates over time, there is evidence that

individuals increase the number, doses, and potency of marijuana

cigarettes. Data have clearly shown that tolerance

[[Page 20071]]

to the stimulus effects of the drug develops which could lead to drug

seeking behavior (Pertwee, 1991; Aceto et al., 1996; Kelly et al.,

1993, 1994; Balster and Prescott, 1992; Mendelson et al., 1976;

Mendelson and Mello, 1985; Mello, 1989). Several studies have reported

that patterns of marijuana smoking and increased quantity of marijuana

smoked were related to social context and drug availability (Kelly et

al., 1994; Mendelson and Mello, 1985; Mello, 1989). There have been,

however, other studies which have demonstrated that the magnitude of

many of the behavioral effects produced by 9-THC

and other synthetic cannabinoids lessens with repeated exposure while

also demonstrating that tolerance did not develop to the euphorigenic

activity, or the “high” from smoked marijuana (Dewey, 1986; Perez-

Reyes et al., 1991). Recent electrophysiological data from animals

suggests that the response of VTA dopamine neurons do not diminish

during repeated exposure to cannabinoids, and that this may underlie

the lack of tolerance to the euphoric effects of marijuana even with

chronic use (Wu & French, 2000).

    The problems of psychological dependence associated with marijuana

(THC) abuse are apparent from DAWN reports and survey data from the

National Household Survey on Drug Abuse and the Monitoring the Future

study. These databases show that the incidence of chronic daily

marijuana use and adverse events associated with its use are

increasing, especially among the young. At the same time, perception of

risk has decreased and availability is widespread (cf., NIDA, 1996).

These factors contribute to perpetuating the continued use of the

marijuana.

(8) Whether The Substance Is an Immediate Precursor of a Substance

Already Controlled Under This Subchapter.

    According to the legal definition, marijuana (Cannabis sativa L.)

is not an immediate precursor of a scheduled controlled substance.

However, cannabidiol is a precursor for delta-9-tetrahydrocannabinol, a

Schedule I substance under the CSA.

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