DEA/OD/ODE 1 September 2010

Basis for the Control of Generic equivalents of Marinol® 

in Schedule III of the Controlled Substances Act

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

Administration, Washington DC 20537

September 2010

INTRODUCTION

The U.S. Drug Enforcement Administration (DEA) has received four petitions 

from companies that have products that are currently the subject of Abbreviated New 

Drug Applications (ANDAs) filed with the U.S. Food and Drug Administration (FDA). 

Each product is a generic formulation of Marinol® and contains dronabinol, the (-) 

isomer of delta-9-(trans)-tetrahydrocannabinol (THC), which is a schedule I controlled 

substance. These petitions each request amendments to Controlled Substances Act 

(CSA) regulations that would have the effect of transferring the proposed generic 

Marinol® product from schedule I to schedule III.

At present, the only formulation containing dronabinol that is in a schedule 

other than schedule I is the following, as set forth in 21 CFR 1308.13(g)(1) as schedule 

III: 

“Dronabinol (synthetic) in sesame oil and encapsulated in a soft gelatin capsule 

in a U.S. Food and Drug Administration approved product.”

While the petitioners cite that their generic products are bioequivalent to 

Marinol®, their products do not meet the current schedule III definition provided above. 

Therefore, these firms have requested that 21 CFR 1308.13(g)(1) be expanded to include: 

(1) both naturally-derived or synthetically produced dronabinol; and (2) both hard or soft 

gelatin capsules.

In response to these petitions, DEA prepared several scheduling review 

documents based upon petitioner-provided data. On June 22, 2007 and August 15, 2007, 

these analyses were submitted to the Department of Health and Human Services (DHHS) 

with requests for scientific and medical evaluation and scheduling recommendations. 

The submissions to DHHS also requested that they consider (1) whether dronabinol 

extracted from Cannabis sativa (i.e. naturally-derived) , is identical to syntheticallyproduced dronabinol found in Marinol®; and (2) whether a formulation encapsulated in 

hard gelatin capsules, instead of soft gelatin capsules, changes a product’s abuse 

potential.

On March 17, 2010 and June 1, 2010, the Assistant Secretary for Health, DHHS,

sent the Deputy Administrator of DEA scientific and medical evaluations and letters 

recommending that FDA-approved drug products containing dronabinol (both naturallyderived or synthetic) in sesame oil in a gelatin capsule (either hard or soft gelatin) be 

placed into schedule III of the CSA. Enclosed with the March 17, 2010 letter, was a 
DEA/OD/ODE 2 September 2010

document prepared by the FDA entitled, “Basis for the Recommendation to Control 

FDA-Approved Drug Products Containing Synthetic Dronabinol in Sesame Oil in a Hard 

Gelatin Capsule to Schedule III of the Controlled Substances Act.” The June 1, 2010

letter included a document entitled, “Basis for the Recommendation to Reschedule FDAApproved Drug Products Containing Naturally-Derived Dronabinol in Sesame Oil in a 

Gelatin Capsule to Schedule III of the Controlled Substances Act.” These documents

contained a review of the factors which the CSA requires the Secretary to consider 21 

U.S.C. 811(b).

The following is a summary of each the factors that the CSA requires to be 

considered pursuant to 21 U.S.C. 811(b):

FACTOR 1. ITS ACTUAL OR RELATIVE POTENTIAL FOR ABUSE

Generic products that reference Marinol® have the same Active Pharmaceutical 

Ingredient (API) (e.g. dronabinol) as that found in Marinol®, an FDA-approved schedule III 

drug product, similar chemistry, pharmacology, and pharmacokinetics and therefore have 

similar potential for abuse. Dronabinol, the (-) isomer of delta-9-(trans)-

tetrahydrocannabinol (THC), is a schedule I controlled substance. It is an agonist at 

cannabinoid receptors and has a recognized abuse potential. (see factor 2, below). 

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

the CSA* suggests the following points in determining whether a particular drug or 

substance has a potential for abuse:

a. Individuals are taking the substance in amounts sufficient to create a hazard to 

their health or to the safety of other individuals or to the community.

b. There is significant diversion of the drug or substance from legitimate drug 

channels.

c. Individuals are taking the substance on their own initiative rather than on the 

basis of medical advice from a practitioner licensed by law to administer such 

substance.

d. The substance is so related in its action to a substance already listed as having a 

potential for abuse to make it likely that it will have the same potential for abuse 

as such substance, thus making it reasonable to assume that there may be 

significant diversions from legitimate channels, significant use contrary to or 

without medical advice, or that it has a substantial capability of creating hazards 

to the health of the user or to the safety of the community.

Approved generic drug products that reference Marinol® have the same API 

(dronabinol) as that found in Marinol®, and therefore have similar potentials for abuse. 

The source of the dronabinol, whether naturally-derived or synthetic, does not alter the 

abuse potential of the substance. Additionally, the difference in formulation between the 

soft gelatin capsule of Marinol® and a hard gelatin capsule is not likely to confer any 

differences in abuse potential. Given these similarities, FDA-approved generic drug 

products that reference Marinol®, as well as FDA-approved generic drug products 

containing synthetic dronabinol or naturally derived dronabinol in sesame oil and 
DEA/OD/ODE 3 September 2010

encapsulated in a hard or soft gelatin capsules, will be similar to Marinol® in terms of the 

amounts taken by individuals and the impact on the community resulting from the 

products’ diversion from legitimate drug channels or their use outside of legitimate 

medical practice.

*Comprehensive Drug Abuse Prevention and Control Act of 1970. H.R. Rep. No. 91-

1444, 91st Cong.. Sess. I (1970) reprinted in U.S.C.C.A.N. 4566,4603.

FACTOR 2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECT

FDA approved generic products that reference Marinol® have the same API 

(dronabinol) as that found in Marinol®, an FDA-approved schedule III drug product, similar 

chemistry, pharmacology, and pharmacokinetics. Dronabinol, the (-) isomer of delta-9-

(trans)-tetrahydrocannabinol (THC), is a schedule I controlled substance. The source of the 

dronabinol, whether naturally-derived or synthetic, does not alter the pharmacological effect 

of the substance. Additionally, the difference in formulation between soft gelatin capsule of 

Marinol® and a hard gelatin capsule is not likely to confer any differences in 

pharmacological effect. 

A. Neurochemistry and Pharmacology of Dronabinol

Dronabinol is a cannabinoid that can be derived naturally from cannabis as well 

as by a synthetic chemical process. Dronabinol is considered the major psychoactive 

cannabinoid constituent of cannabis (Wachtel Ct al., 2002). The structure and function of 

dronabinol was first described in 1964 by Gaoni and Mechoulam. Two cannabinoid 

receptors, CB1 and CB2 have been characterized (Piomelli, 2005).

Autoradiographic studies have provided information on the distribution of 

cannabinoid receptors. CB1 receptors are found in the basal ganglia, hippocampus and 

cerebellum of the brain (Howlett et al., 2004) as well as in the immune system. It is 

believed that the localization of these receptors may explain cannabinoid interference 

with movement coordination and effects on memory and cognition. Concentration of CB1

receptors is considerably lower in peripheral tissues than in the central nervous system 

(Henkerham et al., 1990 and 1992). CB2 receptors are found primarily in the immune 

system, predominantly in B lymphocytes and natural killer cells (Bouaboula et al., 1993). 

It is believed that the CB2 -type receptor is responsible for mediating the immunological 

effects of cannabinoids (Galiegue et a., 1995). However, CB2 receptors also have recently 

been localized in the brain, primarily in the cerebellum and hippocampus (Gong et al, 

2006).

Dronabinol displays similar affinity for CB1 and CB2 receptors, but behaves as a 

weak agonist for CB2 receptors, based on inhibition of adenylate cyclase. The 

identification of synthetic cannabinoid ligands that selectively bind to CB2 receptors, but 

do not have the typical dronabinol-like psychoactive properties suggests that the 

psychotropic effects of cannabinoids are mediated through the activation of CB1 (Hanus 

et al., 1999). Naturally-occurring cannabinoid agonists, such as dronabinol, and the 

synthetic cannabinoid agonists such as WIN-55,212-2 and CP-55,940, produce the classic 

cannabinoid effects of hypothermia, analgesia, hypoactivity and cataplexy, in addition to 

their psychoactive effects.
DEA/OD/ODE 4 September 2010

B. Central Nervous System Effects

Human Physiological and Psychological Effects

Subjective Effects

The physiological, psychological and behavioral effects of dronabinol vary among 

individuals. Common responses to cannabinoids, as described by Adams and Martin 

(1996) and others (Hollister 1986a, 1988a) are listed below:

1) Dizziness, nausea, tachycardia. facial flushing, dry mouth and tremor initially

2) Merriment, happiness and even exhilaration at high doses

3) Disinhibition, relaxation, increased sociability, and talkativeness

4) Enhanced sensory perception, giving rise to increased appreciation of music, 

art and touch

5) Heightened imagination leading to a subjective sense of increased creativity

6) Time distortions

7) Illusions, delusions and hallucinations, especially at high doses

8) Impaired judgment, reduced co-ordination and ataxia, which can impede 

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

9) Emotional liability, incongruity of affect, dysphoria, disorganized thinking, 

inability to converse logically, agitation, paranoia, confusion, restlessness, 

anxiety, drowsiness and panic attacks, especially in inexperienced users or in 

those who have taken a large dose

10) Increased appetite and short-term memory impairment

These subjective responses to cannabinoids are pleasurable to many humans and 

are associated with drug-seeking and drug-taking (Maldonado, 2002).

Animal behavioral effects

Self-Administration

Self-administration is a method that assesses whether a drug produces rewarding 

effects that increase the likelihood of behavioral responses in order to obtain additional 

drug. Drugs that are self-administered by animals are likely to produce rewarding effects 

in humans, which is indicative of abuse liability. Generally, a goad correlation exists 

between those drugs that are self-administered by rhesus monkeys and those that are 

abused by humans (Blaster and Bigelow, 2003).

Interestingly, self-administration of hallucinogenic-like drugs, such as 

cannabinoids, LSD, and mescaline, has been difficult to demonstrate in animals 

(Yanagita, 1980). However, when it is known that humans voluntarily consume a 

particular drug (such as cannabis) for its pleasurable effects, the inability to establish selfadministration with that drug in animals has no practical importance in the assessment of 

abuse potential. This is because the animal test is a predictor of human behavioral 

response in the absence of naturalistic data.
DEA/OD/ODE 5 September 2010

The scientific literature generally reports that naïve animals do not self-administer 

cannabinoids unless they have had previous experience with other drugs of abuse. 

However, when squirrel monkeys are first trained to self-administer intravenous cocaine, 

they continue to bar-press at the same rate as when dronabinol is substituted for cocaine, 

at doses that are comparable to those used by humans who smoke cannabis (Tanda et al., 

2000). This effect is blocked by drugs with cannabinoid receptor antagonist properties, 

such as rimonabant. New studies show that monkeys without a history of any drug 

exposure can be successfully trained to self-administer dronabinol intravenously 

(Justinova et al., 2003).

These data demonstrate that under specific pretreatment conditions, an animal 

model of reinforcement by cannabinoids now exists for future investigations. Rats selfadminister dronabinol when it is applied intracerebroventricularly (i.c.v.), but only at the 

lowest doses tested (0.01-0.02 microgram/infusion) (Braida et al, 2004). This effect is 

antagonized by rimonabant and by the opioid antagonist naloxone (Braida et al., 2004).

There may be a critical dose-dependent effect, though, since aversive effects, 

rather than reinforcing effects, are described in rats that receive high doses of dronabinol 

(Sanudo- Pena et al., 1997). Rimonabant reverses these aversive effects.

Conditioned Place Preference

Conditioned place preference (CPP) is a less rigorous method than selfadministration of determining whether drugs have rewarding properties. In this 

behavioral test, animals are given the opportunity to spend time in two distinct 

environments: one where they previously received a drug and one where they received a 

placebo. If the drug is reinforcing, animals choose to spend more time in the environment 

paired with the drug than the one paired with the placebo, when both options are

presented simultaneously.

Animals show CPP to dronabinol, but only at the lowest doses tested (0.075-0.75 

mg/kg, i.p.) (Braida et al., 2004). This effect is antagonized by rimonabant, as well as by 

naloxone (Braida et al., 2004).

Drug Discrimination Studies

Drug discrimination is a method in which animals indicate whether a test drug 

produces physical or psychic perceptions similar to those produced by a known drug of 

abuse. In this test, an animal learns to press one bar when it receives the known drug of

abuse and another bar when it receives placebo. A challenge session with the test drug 

determines which of the two bars the animal presses more often, as an indicator of 

whether the test drug is like the known drug of abuse.

Animals, including monkeys and rats (Gold et at., 1992), as well as humans 

(Chait, 1988), can discriminate cannabinoids from other drugs or placebo. Discriminative 

stimulus effects of dronabinol are pharmacologically specific for cannabinoids (Balster 

and Prescott, 1992, Barrett et al., 1995, Browne and Weissman, 1981, Wiley Ct al., 1993, 

Wiley et al., 1995). Additionally, the major active metabolite of dronabinol, 11-hydroxydelta-9-THC, also generalizes to the stimulus cue elicited by dronabinol (Browne and 

Weissman, 1981).
DEA/OD/ODE 6 September 2010

The discriminative stimulus effects of the cannabinoid group appear to provide 

unique effects because stimulants, hallucinogens, opioids, benzodiazepines, barbiturates, 

NMDA antagonists and antipsychotics do not fully substitute for dronabinol.

C. Tolerance to the Effects of Dronabinol

Tolerance is a state of adaptation in which exposure to a drug induces changes 

that result in a diminution of one or more of the drug’s effects over time (American 

Academy of Pain Medicine, American Pain Society and American Society of Addiction 

Medicine consensus document, 2001). The presence of tolerance does not determine 

whether a drug has abuse potential, in the absence of other abuse indicators such as 

reinforcing or rewarding properties.

Tolerance to the psychotomimetic and amnesic effects of dronabinol develops in 

humans following chronic exposure (D’Souza et al., 2008). Tolerance also develops in 

humans to the cardiovascular and autonomic changes, decreased intraocular pressure, and 

sleep alterations induced by dronabinol (Jones et al., 1981). Down-regulation of 

cannabinoid receptors has been suggested as the mechanism underlying tolerance to the 

effects of dronabinol (Wu Ct at., 2008, Rodriguez de Fonseca et al., 1994, Oviedo et al., 

1993).

However, in performance tasks, humans have a variable response to chronic use 

of cannabinoids. In long-term cannabis users, performance on neurocognitive tasks such 

as perceptual motor control and dual task processing following administration of 

dronabinol was not reduced compared to moderate cannabis users (Ramaekers et al., 

2008). Additionally, reaction times are not altered by administration of dronabinol in long 

term cannabis users (Block and Wittenborn, 1985). This may be related to electro 

physiological data showing that the ability of dronabinol to increased neuronal firing in 

the ventral tegmental area (a region known to play a critical role in drug reinforcement 

and reward) is not reduced following chronic administration of the drug (Wu and French, 

2000).

FACTOR 3. THE STATE OF CURRENT SCIENTIFIC KNOWLEDGE 

REGARDING THE DRUG OR OTHER SUBSTANCE

The third factor DEA is required to consider is the current scientific knowledge 

regarding the drug or other substance. However, since approved generic products that 

reference Marinol® have the same API (dronabinol), they have similar chemistry, 

pharmacology, and pharmacokinetics as Marinol®, an FDA-approved schedule III drug 

product.

A. Chemistry

The active ingredient in Marinol® and its generic drug products is synthetic 

dronabinol. Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8, 

10a-tetrahydro 6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-1-ol. Dronabinol is a 

naturally occurring component of Cannabis sativa L. (Marijuana).

Dronabinol is a light yellow resinous oil that is sticky at room temperature and 

softens upon refrigeration. Its molecular formula is C21H30O2 and it has a molecular 
DEA/OD/ODE 7 September 2010

weight of 314.47. Dronabinol is insoluble in water but is very soluble in sesame oil. It has 

a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.

Dronabinol in Marinol® and the generic drug products that reference Marinol® 

are formulated with sesame oil. The three dosage formulations of Marinol® contain 2.5, 

5 and 10 mg of dronabinol in sesame oil in soft gelatin capsules. This formulation is 

intended for oral administration only. It is difficult to separate dronabinol in pure form 

from sesame oil because of these two substances have similar physicochemical 

properties. Intravenous use is difficult because an aqueous solution of pure dronabinol 

cannot be created easily. Additionally, attempts to smoke dronabinol formulated in 

sesame oil results in an undesirable production of soot and oil ignition, based on the 

presence of long-chain hydrocarbons in the sesame oil. The ability of sesame oil to catch 

fire easily is verified by its historical use as a lamp oil (Copley et al, 2005).

B. Human Pharmacokinetics

The human pharmacokinetics of dronabinol in Marinol® capsules are described in 

the drug label. Clinical pharmacology assessment ensures that generic drug products that 

reference Marinol® are bioequivalent to Marinol®, thus meeting the requirement for 

generic drug approval by FDA.

Following single oral doses, synthetic dronabinol is almost completely absorbed 

(90 to 95%). However, after dronabinol absorption, first-pass hepatic elimination from 

blood leads to a low and variable bioavailability, ranging from 5 to 20 percent. 

Dronabinol is very lipid soluble, leading to a large apparent volume of distribution 

(approximately 10 L/kg) and efficient delivery to the brain. The plasma protein binding 

of dronabinol and its metabolites is approximately 97%.

The pharmacokinetics of synthetic dronabinol after single doses (2.5, 5 or 10 mg) 

and multiple doses (2.5, 5 or 10mg given twice a day; BID) were studied in healthy 

volunteers and are reported in the drug label for Marinol®, as shown in Table 2 below:

Table 2: Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in 

Healthy Volunteers

Mean (SD) P Parameter Values

BID Cmax Median Tmax AUC(O-12)

Dose ng/mL (range), hr ng•hr/mL

2.5mg 1.32 (0.62) 1.00 (0.50-4.00) 2.88 (1.57)

5 mg 2.96 (1.81) 2.50 (0.50-4.00) 6.16 (1.85)

10mg 7.88 (4.54) 1.50 (0.50-3.50) 15.2 (5.52)

A slight increase in dose proportionality on mean Cmax and AUC (0-12) of 

dronabinol was observed with increasing dose over the dose range studied. The onset of 

effects after oral administration of dronabinol is 30-90 mm, with a peak at approximately 

2-3 hours and continuing effects for 4-12 hours (Grotenhermen, 2003; Adams and Martin 

1996; Agurell et al. 1984, 1986). Following oral administration of radioactive-labeled 

dronabinol, plasma levels of dronabinol are low relative to those levels after smoking or 
DEA/OD/ODE 8 September 2010

intravenous administration. There is inter- and intra-subject variability, even when 

repeated dosing occurs under controlled conditions.

Cannabinoid metabolism is extensive. Dronabinol is metabolized via microsomal 

hydroxylation to both active and inactive metabolites (Lemberger et al., 1970, 1972a, 

1972b; Agurell et al., 1986; Hollister, 1988a) of which the primary active metabolite is 

11 -hydroxy-delta-9-THC. This metabolite is approximately equipotent to dronabinol in 

producing cannabinoid-like subjective effects (Agurell et al., 1986, Lemberger and 

Rubin, 1975). In addition to II -hydroxy-delta -THC, some inactive carboxy metabolites 

have terminal half-lives of 50 hours to 6 days or more. The majority of the absorbed 

dronabinol dose is eliminated in feces, and about 33 percent in urine. Dronabinol enters 

enterohepatic circulation and undergoes hydroxylation and oxidation to 11-nor-9-

carboxy-delta-9-THC. The glucuronide is excreted as the major urine metabolite along 

with about 18 nonconjugated metabolites.

According to the drug label for Marinol®, the elimination phase of dronabinol 

can be described using a two compartment model with an initial (alpha) half-life of about 

4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its large volume of 

distribution, dronabinol and its metabolites may be excreted at low levels for prolonged 

periods of time. The terminal half-life of dronabinol is estimated to range from 

approximately 20 hours to as long as 10 to 13 days (Hunt and Jones, 1980), though 

reported estimates vary as expected with any slowly cleared substance and the use of 

assays of variable sensitivities.

Dronabinol and its biotransformation products are excreted in both feces and 

urine. Biliary excretion is the major route of elimination with about half of a radiolabeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 

15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the 

feces.

Following single dose administration, low levels of dronabinol metabolites have 

been detected for more than 5 weeks in the urine and feces.

FACTOR 4. ITS HISTORY AND CURRENT PATTERN OF ABUSE 

The fourth factor DEA is required to consider is the history and current pattern of 

abuse. Since drug products that contain naturally-derived dronabinol, or products that 

contain synthetic dronabinol in sesame oil in a hard gelatin capsule, are not currently 

marketed, no information is available regarding a pattern of abuse.

However, generic drug products that reference Marinol® have the same API 

(synthetic dronabinol) and similar chemistry and pharmacokinetics as Marinol®, an 

FDA-approved Schedule III drug product. Dronabinol is an agonist at cannabinoid 

receptors and has a known abuse potential in humans (see Factor 2, above).

The eight factor analysis and recommendation for placement of Marinol® into 

Schedule III (HHS, 1998) stated that, “A pattern of abuse of Marinol® has not been 

uncovered. Only sporadic reports of small amount of diversion have been documented. 

Comparisons of patterns of abuse [between marijuana and Marinol] illustrate that there is 

considerable abuse of marijuana and virtually none of Marinol®. One factor contributing 
DEA/OD/ODE 9 September 2010

to these few occurrences of diversion and abuse is no doubt the limited general 

availability of Marinol®, worldwide or nationally, relative to that of marijuana.” Thus, it 

is expected that the FDA-approved generic drug products that reference Marinol®, as 

well as generic drug products approved for marketing by FDA that contain synthetic 

dronabinol in sesame oil in a hard gelatin capsule, will have a similar pattern of abuse to 

that of Marinol®. 

The abuse potential of generic drug products approved pursuant to an ANDA is 

considered to be similar to the Reference Listed Drug (RLD) based on equivalent 

quantities of the API present in the dosage form. Thus, the abuse potential of the 

dronabinol in sesame oil in approved ANDAs for generic drug products that reference 

Marinol® will be similar regardless of whether the API is from synthetic or natural 

source, or encapsulated in hard or soft gelatin capsules, since the two formulations are 

considered to be similar. Given these similarities, generic drug products that reference 

Marinol® will have a similar pattern of abuse as that of Marinol®. 

FACTOR 5. THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE

The fifth factor DEA is required to consider is the scope, duration and significance of 

abuse. Since drug products that contain naturally-derived dronabinol, or products that 

contain synthetic dronabinol in sesame oil in a hard gelatin capsule, are not currently 

marketed, no information is available regarding a pattern of abuse. Once again, approved 

generic products that reference Marinol® have the same API (dronabinol) and similar 

chemistry, pharmacology, and pharmacokinetics as Marinol®, an FDA-approved schedule III 

drug product.

Approved ANDAs for generic drug products are considered to be similar in 

activity to the RLD based on equivalent quantities of the API present in the dosage form.

The eight factor analysis and recommendation for placement of Marinol® into 

Schedule III (HHS, 1998) stated that. “Adverse reaction reports have failed to generate 

any reports of drug abuse, dependence, withdrawal, overdose (intentional or accidental) 

or tolerance development” with Marinol®. Thus, the abuse potential of synthetic 

dronabinol in sesame oil in approved ANDAs for generic drug products that reference 

Marinol® will be similar regardless of whether the API is encapsulated in hard or soft 

gelatin capsules. Given these similarities, generic drug products that reference Marinol® 

will have a scope, duration, and significance of abuse similar to that of Marinol®. 

FACTOR 6. WHAT, IF ANY, RISK THERE IS TO THE PUBLIC HEALTH

The sixth factor DEA must consider is whether there is any risk to the public health 

from FDA-approved generic drug products that contain naturally-derived dronabinol, or 

products that contain synthetic dronabinol in sesame oil in a hard gelatin capsule and 

reference Marinol®. The public health risks can be assessed by evaluating the adverse 

events and overdose symptoms associated with Marinol®, since dronabinol is the API in 

both Marinol® and in generic drug products that reference Marinol®. 

A. Adverse Events
DEA/OD/ODE 10 September 2010

The AEs associated with the use of Marinol® are described in the product label. 

Central nervous system AEs include euphoria, amnesia, anxiety, confusion, 

depersonalization, hallucination, paranoia, somnolence and abnormal thinking. Peripheral 

AEs include asthenia, palpitations, vasodilation, abdominal pain, nausea, and vomiting. 

For purposes of assessing abuse potential, euphoria is a significant AE. However, the 

other listed AEs can contribute to medical emergencies when individuals use Marinol® 

for abuse purposes.

B. Overdose

The product label for Marinol® states that the signs and symptoms of overdose 

include drowsiness, euphoria, heightened sensory awareness, altered time perception, 

reddened conjunctiva, dry mouth, tachycardia, memory impairment, mood alteration, 

urinary retention, decreased motor coordination, lethargy, postural hypotension, panic 

and seizure disorders. There is no known antidote for Marinol® overdose and the 

treatment is appropriate supportive care.

FACTOR 7. ITS PSYCHIC OR PHYSIOLOGICAL DEPENDENCE LIABILITY

The seventh factor DEA must consider is the psychic and physiologic dependence 

liability of FDA-approved generic drug products that contain naturally-derived dronabinol, or 

products that contain synthetic dronabinol in sesame oil in a hard gelatin capsule and 

reference Marinol®. Given that the API in these products is dronabinol, the dependence 

liability is likely the same.

Physical dependence is a state of adaptation manifested by a drug class-specific 

withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing 

blood level of the drug and administration of an antagonist (American Academy of Pain 

Medicine, American Pain Society and American Society of Addiction Medicine 

consensus document, 2001).

In chronic cannabis users, a withdrawal syndrome was described that consists of 

restlessness, irritability, mild agitation, insomnia, sleep EEG disturbances, nausea and 

cramping that resolves within a few days (Haney et al, 1999). This indicates that cannabis 

produces physical dependence. Similarly, a review of clinical studies on cannabis 

discontinuation led to the conclusion that cannabis produces a withdrawal syndrome that 

includes such symptoms as sleep difficulties, strange dreams, decreased appetite, 

decreased weight, anger, irritability and anxiety (Budney et al., 2004). Based on clinical 

descriptions, this syndrome appears to be mild compared to classical alcohol and 

barbiturate withdrawal syndromes, which can include more serious symptoms including 

agitation, paranoia, and seizures.

A recent study comparing cannabis and tobacco withdrawal symptoms in humans 

demonstrates that the magnitude and time course of the two withdrawal syndromes are 

similar (Vandrey et al., 2005). Lane et al. (1998) describes milder cases of dependence 

including symptoms that are comparable to those from caffeine withdrawal, including 

decreased vigor, increased fatigue, sleepiness, headache, and reduced ability to work. The 

marijuana withdrawal syndrome is reported in adolescents admitted for substance abuse 
DEA/OD/ODE 11 September 2010

treatment or in individuals who were given marijuana on a daily basis during research 

conditions.

The production of an overt withdrawal syndrome in animals following chronic 

dronabinol administration has been variably demonstrated under conditions of natural 

discontinuation. This may be the result of the slow release of cannabinoids from adipose 

storage, as well as the presence of the major psychoactive metabolite, 11-hydroxy-delta9-THC. Investigators showed such a withdrawal syndrome in monkeys following the 

termination of cannabinoid administration: the behaviors included transient aggression, 

anorexia, biting, irritability, scratching and yawning (Budney et al., 2004). However, in 

rodents treated subacutely with dronabinol, administration of rimonabant, a drug with 

cannabinoid antagonist properties, produced pronounced withdrawal symptoms including 

wet dog shakes (Breivogel et al., 2003).

FACTOR 8. WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR 

OF A SUBSTANCE ALREADY CONTROLLED UNDER THE CSA

Generic drug products that contain naturally-derived dronabinol or products that 

contain synthetic dronabinol in sesame oil in a hard gelatin capsule, and reference 

Marinol®, contain the API dronabinol. Dronabinol is not an immediate precursor of any 

substance controlled under the CSA, as defined in 21 USC 811(e).

Summary and Conclusions of the 8-Factor Analysis

21 U.S.C. § 812(b) requires the evaluation of a substance’s abuse potential, legitimate 

medical use, and safety or dependence potential for placement in the CSA as a controlled 

substance. Upon consideration of the eight-factors required for control of a substance (21 

U.S.C. § 811(c)), and the scientific and medical evaluation and scheduling recommendation 

by DHHS, DEA finds that Dronabinol, as summarized below, meets the three criteria for 

placement in schedule I of the CSA under 21 U.S.C. § 812(b).

Based on the recommendations of the Assistant Secretary for Health, received in

accordance with section 201(b) of the Act [21 U.S.C. 811(b)], and the independent 

review of the available data by DEA, the Deputy Administrator of DEA, pursuant to

sections 201(a) and 201(b) of the Act [21 U.S.C. 811(a) and 811(b)], finds that FDAapproved generic dronabinol products, both naturally-derived or synthetically produced, 

in sesame oil and encapsulated in both hard gelatin or soft gelatin capsules meet the 

criteria for placement in schedule III set in 21 U.S.C. 812(b), as follows:

A. The drug or other substance has a potential for abuse less than the 

drugs or other substances in Schedule II.

FDA-approved generic drug products that contain dronabinol (both naturallyderived or synthetically produced) in sesame oil in a gelatin capsule (both hard or soft 

gelatin) and reference Marinol®, have a similar potential for abuse as Marinol®, a 

schedule III drug product and have similar chemistry and pharmacokinetics as similar 

formulations in sesame oil.
DEA/OD/ODE 12 September 2010

B. The drug or other substance has a currently accepted medical use in 

treatment in the United States.

Marinol® was initially approved by FDA in 1985. When drug products that 

reference Marinol® receive FDA approval, they will have a currently accepted medical 

use in the United States.

C. Abuse of the drug or other substance may lead to moderate or low 

physical dependence or psychological dependence and such 

dependence would be less than the drugs or other substances in 

Schedule II.

The withdrawal syndrome associated with dronabinol, the API in Marinol®, 

produces symptoms in humans such as restlessness, irritability, mild agitation, anxiety, 

anger, insomnia, sleep EEG disturbances, nausea, decreased appetite and decreased 

weight. Since a withdrawal syndrome is indicative of physical dependence, it is 

reasonable to conclude that generic dronabinol products (both naturally-derived or 

synthetically produced, and in hard or soft gelatin capsules) in sesame oil, will also 

produce physical dependence similar to those produced by Marinol®.
DEA/OD/ODE 13 September 2010

REFERENCES

Adams, l.B., and Martin, B.R. Cannabis: Pharmacology and toxicology in animals and 

humans. Addiction 1996, 91(ll):1585-1614.

Agurell, S., Dewey, W.L., and Willett, R.E., eds. The Cannabinoids: Chemical, 

Pharmacologic, and Therapeutic Aspects. New York: Academic Press, 1984.

Agurell, S.; Haildin, M.; Lindgren, J.E.; Ohlsson, A.; Widman, M.; Gillespie, H.; and 

Hollister, L. Pharmacokinetics and metabolism of delta I -tetrahydrocannabinol and other 

cannabinoids with emphasis on man. Pharmacol Rev 1986, 38(1), 21-43.

American Academy of Pain Medicine, American Pain Society and American Society of 

Addiction Medicine Consensus Document. Definitions related to the use of opioids for 

the treatment of pain. 2001.

Baister, R.L., Prescott, W.R., delta discrimination in rats as a model for cannabis 

intoxication. Neurosci. & Biobchav. Rev. 1992, 16(1), 55-62.

Baister RL and Bigelow GE (2003). Guidelines and methodological reviews concerning 

drug abuse liability assessment. Drug and Alcohol Dependence 70: Si 3-S40.

Barnelt, G.; Licko, V.; and Thompson, T. Behavioral pharmacokinetics of marijuana. 

Psychopharmacology 1985, 85(1), 51-56.

Block RI, Wittenborn JR. Marijuana effects on associative processes. 

Psychopharmacology (Ben). I 985;85(4):426-30.

Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, Le Fur 0, Casellas 

P. Cannabinoid-receptor expression in human leukocytes. Eur J Biochem. 1993 May 

15;214(l):

Braida D, losue S. Pegorini S, Sala M. Delta9-tetrahydrocannabinol-induced conditioned 

place preference and intracerebroventricular self-administration in rats. Eur 3 Pharmacol. 

2004 Dec 3;506(1):63-9.

Breivogel CS, Scates SM, Beletskaya 10, Lowery OB, Aceto MD, Martin BR. The 

effects of delta9-tetrahydrocannabinol physical dependence on brain cannabinoid 

receptors. Eur 3 Pharmacol. 2003 Jan 17;459(2-3):139-50.

Browne RG, Weissman A. Discriminative stimulus properties of delta 9-

tetrahydrocannabinol: mechanistic studies. J Clin Pharmacol. 1981 Aug-Sep;21(8-9 

Suppi) :227S-234S.

Budney AJ, Hughes JR. Moore BA, Vandrey R. Review of the validity and significance 

of cannabis withdrawal syndrome. Am J Psychiatry. 2004 Nov;161(1 l):1967

Chait LD, Evans SM, Grant KA, Karnien JB, Johanson CE, Schuster CR. Discriminative 

stimulus and subjective effects of smoked marijuana in humans. Psychopharmacology 

(Ben). 1 988;94(2):206- 12.

Copley MS, Bland HA, Rose P Horton M, Evershed RP. Gas chromatographic, mass 

spectrometric and stable carbon isotopic investigations of organic residues of plant oils 
DEA/OD/ODE 14 September 2010

and animal fats employed as illuminants in archaeological lamps from Egypt. Analyst. 

2005 Jun; I 30(6):860-7 1.

D’Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, Perry E, 

Krystal J. Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol 

in frequent users of cannabis. Neuropsychopharmacology. 2008 Sep;33(l0):2505-16.

Galiegue S, Mary S, Marchand 3, Dussossoy D, Carriere D, Carayon P. Bouaboula M, 

Shire D, Le Fur G, Casellas P. Expression of central and peripheral cannabinoid receptors 

in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995 Aug 

15;232(l):54-61.

Gaoni, Y., Mechoularn, R. Isolation, structure, and partial synthesis of an active 

constituent of hashish. J. Am. Chem. Soc. 1964, 86, 1646-1947.

Gold LH, Balster RL, Barrett RL, Britt DI, Martin BR. A comparison of the 

discriminative stimulus properties of delta 9-tetrahydrocannabinol and CP 55,940 in rats 

and rhesus monkeys. 3 Pharmacol Exp Ther. 1992 Aug;262(2):479-86.

Gong H ir, Tashkin DP, Simmons MS, Calvarese B, Shapiro BJ. Acute and subacute 

bronchial effects of oral cannabinoids. Clin Pharmacol Ther. 1984 Jan;35(l):26-32.

Grotenhermcn F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin 

Pharmacokinet. 2003 ;42(4):327-60.

Haney M, Ward AS, Corner SD, Foltin RW, Fischman MW. Abstinence symptoms 

following smoked marijuana in humans. Psychopharmacology (Ben) 1999, 141 (4):395-

404

Hanus, L., Breuer, A., Tchilibon, S., Shiloah, S., Goldenberg, D., Horowitz, M., Pertwee, 

R.G., Roos, R. A., Mechoulam, R., Fride, E. HU-308: a specific agonist for CB(2), a 

peripheral Cannabinoid receptor. Proc. Nati. Acad. Sd. USA 1999, 96, 14228-33.

Health and Human Services. Basis for the Recommendation for Rescheduling Marinol® 

Capsules from Schedule II to Schedule 111 of the Controlled Substances Act (CSA). 

1998.

Herkenham, M. Cannabinoid receptor localization in brain: Relationship to motor and 

reward systems. In: Kalivas, P.W., and Samson, H.H., eds. The neurobiology of drug and 

alcohol addiction. Ann N Y Acad Sci 1992, 654, 19-32.

Herkenham, M., Lynn, A. B., Little, M. D., Johnson, M. R., Melvin, L. S., de Costa, B. 

R., Rice, K. C. Cannabinoid receptor localization in Brain. Proc. Natl. Acad. Sd. U S A. 

1990, 87, 1932-1936.

Hollister, L.E. Health aspects of cannabis. Pharmacological Rev. 1986, 38, 1-20. 

Hollister, L.E. Cannabis. (Lit, rev.). Acta Psychiatr Scand (Suppl) 1988, 78, 108-118.

Flowlett AC, Breivogel CS, Childers SR. Deadwyler SA, Hampson RE, Porrino LI. 

Cannabinoid physiology and pharmacology 30 years of progress. Neuropharmacology. 

2004;47 Suppl 1:345-58

Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man. J 

Pharmacol Exp Ther. 1980 Oct;215(l):35-44.
DEA/OD/ODE 15 September 2010

Jones, R.T.; Benowitz, N.L.; and 1-lerning, RI. Clinical relevance of cannabis tolerance 

and dependence. J Clin Pharmacol 1981, 21,143S-152S.

Justinova Z, Tanda G, Redhi GH, Goldberg SR. Self-administration of delta9-

tetrahydrocannabinol (TI-IC) by drug naive squirrel monkeys. Psychopharmacology 

(Berl). 2003 Sep;

Lane JD, Phillips-Bute 8G. Caffeine deprivation affects vigilance performance and mood. 

Physiol Behav 1998 65, 171-5

Lemberger L., Silberstein, S. D., Axeirod, J., Kopin, I. J. Marihuana: studies on the 

disposition and metabolism of delta-9-tetrahydrocannabinol in man. Science 1970, 170, 

1320- 1322.

Lemberger L., Weiss, J. L., Watanabe, A. M., Galanter, I. M., Wyatt, R. J., Cardon, P. V. 

Delta-9-tetrahydrocannabinol: temporal correlation of the psychological effects and blood 

levels after various routes of administration. New Eng. J. Med. l972a, 286(13), 685-688.

Lemberger, L., Crabtree, R. E., Rowe, H. M. 1 1-1-Iydroxy-) pharmacology, disposition 

and metabolism of a major metabolite of marihuana in man. Science 1972b, 177, 62-63.

Lemberger L., Rubin A. The physiologic disposition of inarihuana in man, Life Sci. 

1975,17, 1637-42.

Maldonado R. Study of cannabinoid dependence in animals. Pharmacol Ther. 2002 

Aug;95(2): 153-64.

Oviedo, A., Glowa, J., Herkenham, M. Chronic cannabinoid administration alters 

cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain 

Res. 1993, 616, 293-302.

Piomelli D. The endocannabinoid system: a drug discovery perspective. Curr Opin 

Investig Drugs. 2005 Jul;6(7):672-9.

Raniaekers J, Kauert G, Theunissen E, Toennes S, Moeller M. Neurocognitive 

performance during acute THC intoxication in heavy and occasional cannabis users. J 

Psychopharmacol. 2008 Sep 18.

Rodriguez de Fonseca F, Gorriti, M.A., Fernandez-Ruiz, J.J., Palomo, T., Ramos, J.A. 

Downregulation of rat brain cannabinoid binding sites after chronic delta 9-

tetrahydrocannabinoil treatment. Phamacol. Biochem. Behav. 1994, 47 (1), 33-40.

Sanudo-Pena M. C., Tsou, K., Delay, E. R., Hohman, A. G., Force, M., Walker, J. M. 

Endogenous cannabinoids as an aversive or counter-rewarding system in the rat. 

Neurosci. Lett., 223. 125-128, 1997.

Tanda G, Munzar P. Goldberg SR. Self-administration behavior is maintained by the 

psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci. 2000 Nov;3(l 

1):1073-4.

Vandrey RG, Budney AJ, Moore BA, Hughes JR. A cross-study comparison of cannabis 

and tobacco withdrawal. Am J Addict. 2005 Jan-Feb;14(1):54-63.
DEA/OD/ODE 16 September 2010

Wachtel SR, ElSohly MA, Ross SA, Ambre J, de Wit H. Comparison of the subjective 

effects of Delta(9)-tetrahydrocannabinol and marijuana in humans. Psychopharmacology 

(Ben). 2002 Jun;16l(4):331-9

Wiley JL, Barrett RL, Britt DT, Baister RL, Martin BR. Discriminative stimulus effects 

of delta 9-tetrahydrocannabinol and delta 9-1 1 -tetrahydrocannabinol in rats and rhesus 

monkeys. Neuropharmacology. 1993 Apr;32(4):359-65.

Wiley JL, Huffluan JW, Baister RL, Martin BR. Pharmacological specificity of the 

discriminative stimulus effects of delta 9-tetrahydrocannabinol in rhesus monkeys. Drug 

Alcohol Depend. 1995 Nov;40( I ):8 1-6.

Wu DF, Yang LQ, Goschke A, Sturnm R, Brandenburg LO, Liang YJ, Höllt V, Koch T. 

Role of receptor internalization in the agonist-induced desensitization of cannabinoid 

type I receptors. J Neurochem. 2008 Feb;104(4):l 132-43. Epub 2007 Nov 6.

Yanagita, T. Self-administration studies on psychological dependence. Trends in 

Pharmacological Sciences, 1:1, 161-164, 1979-1980.