12/04/98 Acting Deputy Administrator
Drug Enforcement Administration
Washington, DC. 20537
Attention: DEA Federal Register Representative/CCR.
Dear Sir:
The undersigned Jon Gettman and Trans-High Corporation hereby request a hearing in the
matter of the proposed rule for the Rescheduling of Synthetic Dronabinol as published in
the Federal Register, 63 FR 59751.
- (A) Standing.
The Code of Federal Regulations states that the Administrator shall hold a hearing
"if requested by any interested person" (21 CFR S1308.42) who is "adversely
affected or aggrieved" (21 CFR S1301.01 (a)(19)) by a proposed rule. An interested
person may also file a petition to propose or repeal a rule (21 CFR S1301.44 (a)).
Jon Gettman and Trans-High Corporation have filed a petition for the repeal of the
rules placing marijuana, THC, dronabinol, and nabilone in schedules I and II of the
Controlled Substances Act, and for their rescheduling according to rulemaking procedures.
The DEA accepted this petition for filing on July 27, 1995 and notified petitioners of its
referral to the Department of Health and Human Services (DHSS) on December 19, 1997.
Referral of the petition to DHHS certifies Gettman and Trans-High as interested parties in
rule-making proceedings involving any cannabinoid substance, particularly in proceedings
involving the potential rescheduling of a substance, dronabinol, that is included in their
own petition for repeal of administrative rules.
The rescheduling of dronabinol as presently proposed advances interpretive rulings by
DEA that require judicial review and clarification, as well an examination of adjudicative
and other issues upon which these interpretive rulings are based. Failure to intervene in
this case could result in our loss of standing to litigate these issues at a later date
(National Wildlife Fedn. V. Gorsuch, No. 83-5753, United States Court Of Appeals For The
Third Circuit, 744 F.2d 963, 1983). Public comment prior to adoption of a rule is
essential to the integrity of the administrative rulemaking process. (Mason Gen. Hosp. V.
Secretary Of The DHHS, No. 86-1011, United States Court Of Appeals For The Sixth Circuit,
809 F.2d 1220; 1987, United States V. Gavrilovic, Nos. 76-1219, 76-1220, 76-1242, 76-1379,
76-1381, 76-1382, United States Court Of Appeals For The Eighth Circuit, 551 F.2d 1099;
1977). Adjudicative facts are more likely to warrant a hearing than legislative facts
(Broz V. Schweiker, Nos. 81-7140, 81-7143, 81-7336, 81-7370, 81-7466, United States Court
Of Appeals, Eleventh Circuit, 677 F.2d 1351; 1982).
Gettman and Trans-High Corporation are potentially adversely affected by the proposed
rulemaking, due to their general concern for the integrity of the rulemaking process and
their specific concern for issues that may have a bearing on the outcome of their own
petition.
- (B) The following discussion states with particularity the objections and issues
concerning which we wish to be heard.
Marijuana and Marinol contain the same active ingredient, delta-9-THC.
Presently both substances are designated as having a high potential for abuse. The
primary legal distinction between them is that Marinol, unlike marijuana, has an accepted
medical use in the United States and has been determined to be safe for use under medical
supervision.
Marinol is distributed by Roxane Laboratories and owned by Unimed, Inc. In February
1995, Unimed petitioned the Drug Enforcement Administration to change the scheduling of
Marinol under the Controlled Substances Act from Schedule II, its current regulatory
status, to Schedule III (63 FR 59751).
One key legal issue is whether Marinol has a lower potential for abuse relative to
current Schedule I and II substances, including marijuana (21 USC 812 (3)(A)). This raises
a number of important subsidiary issues.
The original placement of Marinol in Schedule II was largely determined by marijuana's
Schedule I status and its implicit designation as a substance with a high potential for
abuse (Letter of Edward Brandt, 8/16/82). Rescheduling Marinol to Schedule III implies
that THC in its pure branded pharmaceutical form has a lower potential for abuse than THC
in its generic, naturally occurring form. Objections to this rescheduling derive in part
from evidence that marijuana and Marinol have at least the same potential for abuse, and
that Marinol has a greater potential for misuse than marijuana.
1. Schedule-I marijuana contains the same psychoactive ingredient as Marinol. The
proprietary chemical in Marinol is named "dronabinol." According to its
distributor, "Dronabinol, delta-9-tetrahydrocannabinol (delta-9-THC), is naturally
occurring and has been extracted from Cannabis sativa L. (marijuana). Dronabinol is also
chemically synthesized and is a light-yellow resinous oil that is . . . formulated in
sesame oil" (Roxane Laboratories, Internet Website). Marinol has at least the abuse
potential that marijuana does.
2. The DHHS evaluation of THC, unchanged by the proposed rescheduling of Marinol, holds
that the two substances have the same potential for abuse (Letter of Edward Brandt,
8/16/82).
3. DHHS has determined in prior cases that rescheduling recommendations that are
inconsistent with the scheduling of other cannabinoid substances should be rejected
(Letter of Ian Macdonald, 4/25/86).
4. Marinol is consumed orally. Unlike THC obtained from the smoking of marijuana, the
oral consumption of THC produces a psychoactive metabolite, 11-OH-delta-9-THC, that
appears in approximately equal concentrations in plasma (Roxane Laboratories, Internet
Website; Physicians' Desk Reference, 1993; United States Pharmacopeial Convention, 1995).
Consequently, Marinol will have stronger effects than an equivalent dosage of THC
delivered via smoked marijuana.
5. When marijuana is smoked, its peak effects occur during the process of consumption,
and typically peak blood-plasma levels occur before smoking is complete (Huestis, M.A.,
1992). By contrast, according to Roxane, "Concentrations of both [dronabinol] and
metabolite peak at approximately 2 to 4 hours after oral dosing and decline over several
days" (Roxane Laboratories, Internet Website).
6. Auto-titration of marijuana is easier than that of Marinol. An effective dose of THC
can be as small as 10 micrograms per kilogram (Agurell, et al, 1985). Depending on an
individual's experience and method of smoking, 10 to 45% of the THC in marijuana is
delivered; the remainder is destroyed by pyrolysis or lost as sidestream smoke (Agurell et
al, 1985). In an oral dose, dronabinol has systemic availability of 10 - 20% compared to
an iv dose (Physicians' Desk Reference, 1993). Marijuana is consumed in forms of varying
potency, averaging between 3 and 4% over the last several years, but is also available in
much higher potencies (Elsholy, M.A., 1996). Marinol is available in 2.5, 5, and 10 mg
capsules (Roxane Laboratories, Internet Website; Physicians' Desk Reference, 1993; United
States Pharmacopeial Convention, 1995). Consumption of marijuana by smoking presents an
interval scale of available dosing options that can be manipulated according to immediate
feedback regarding peak effects, whereas consumption of Marinol is constrained by the
ordinal scale presented by the 3 capsule dosages and the 2-to-4 hour delay for occurrence
of peak effects.
7. In marijuana THC is accompanied by other cannabinoids, including cannabidiol (CBD),
which, while not psychoactive, mediate effects of THC such as tachycardia. Marinol lacks
CBD and may produce slightly more severe adverse effects than marijuana (Personal
Communication, Ethan Russo, 11/13/98).
8. Individuals with experience with both drugs consider Marinol to be both a stronger
drug than smoked marijuana and one with a greater potential for abuse. These observations
are based on experience with titration and potency issues, particularly the additional
effects produced by the psychoactive metabolite (Personal Communications, names withheld).
9. If "abuse" is defined as unapproved or non-medical use, then the actual
abuse of Marinol as a Schedule II drug is not an indicator of its abuse potential as a
more widely available Schedule III drug. The internal cannabinoid-receptor system that is
activated by marijuana and Marinol develops tolerance to many of the effects of THC
(Oviedo et al, 1993). Diminished regulation of Marinol as a Schedule III drug could result
in more extensive use by patients that, because of tolerance, will require far greater
dosage units in circulation and in possession of individual patients. As opportunities for
diversion increase, the actual incidence of abuse could increase--especially if
"abuse" is defined according to the presumptions that form the basis of
marijuana's existing Schedule I status.
10. Marijuana and Marinol both activate the same cannabinoid-receptor system in the
brain. This system has a known and indirect effect on dopamine production that is
associated with the dependence liability of several controlled substances (Tanda et al,
1997). While there are considerable characteristics that differentiate the abuse potential
of other drugs, there are no neurobiological grounds for differentiating the abuse
potential of the THC in marijuana from THC labled "dronabinol" and contained in
Marinol. Furthermore, consistent heavy use of either substance produces a mild withdrawal
syndrome characterized in part by the production of Corticotropin-Releasing Factor (CRF),
a chemical released in the amygdala associated with stress and negative consequences of
withdrawal from alcohol, cocaine, and opiates (Rodriguez de Fonseca, 1997).
11. Nabilone, a product of the Eli Lily Company prescribed as an anti-emetic in Canada,
is pharmacologically similar to THC. Nabilone is a Schedule II substance because its abuse
potential is presumed to be identical to that of marijuana, THC, and Marinol (Letter of
Ian Macdonald, 4/25/85).
12. The Controlled Substances Act specifies various factors that will be considered in
the administrative rule-making process pertaining to any substance, including "its
history and current pattern of abuse" and "the scope, duration, and significance
of abuse" (21 USC 811 (c) (4-5)). The legislative history of this statute indicates
that these factors require consideration of "the social, economic, and ecological
characteristics of the segments of the population involved in such abuse," and
"the social significance and impact of such a decision upon those people. . . that
would be affected by it." In July 1996 the DEA's Office of Diversion Control
published a report on the use of the cannabis plant as a source for industrial raw
materials ("The Manufacture of Cannabis Sativa for Legitimate Applications").
This report considers social, economic, and ecological characteristics of using the
cannabis plant to produce fiber and seed-related products, and determines "the
information collected and reviewed shows that hemp cultivation, within the United States,
would not promise a profitable return on investment." This is an interpretive ruling
by the DEA's Office of Diversion and Control that the threat to public health of the trace
elements of THC present in industrial hemp pose such a potential for abuse, and threat to
public health is so great, as to outweigh any possible benefits to be derived from the
cultivation of cannabis sativa as a source for industrial raw materials. The rescheduling
of dronabinol to Schedule III is inconsistent with DEA's interpretive rulings that the THC
present in industrial hemp subjects it to control under the CSA because of its Schedule I
level of abuse potential. Furthermore, this interpretive ruling disregards general
provisions against de facto rule-making in the guise of policy statements, and statutory
requirements that DEA request such findings as considered in its hemp report from DHHS.
13. "Dronabinol" is defined by its manufacturer as synthetic or natural THC.
The proposed rule addresses the scheduling of "synthetic" dronabinol and implies
that a different standard exists for evaluating the abuse potential of natural and
synthetic versions of the same chemical molecule.
14. The rescheduling of synthetic dronabinol creates a precedent for the rescheduling
of natural dronabinol. Dronabinol will be presumed to have a lower potential for abuse
than the THC that is contained in industrial hemp, according to existing DEA
interpretative rulings. This will lead to the denial of fundamental constitutional rights
to equal protection under the law. Under this proposed rescheduling, Unimed will be
allowed to conduct cultivation research on cannabis sativa plants to provide industrial
raw materials under Schedule III regulations, because these regulations will allow them to
call the active ingredient "dronabinol" rather than THC. On the other hand, any
other company or individual who wants to conduct cultivation research on cannabis sativa
plants to provide industrial raw material must do so under Schedule I regulations, because
the active ingredient in their case is called "THC." How can Marinol, an oral
preparation that exerts effects which are demonstrably stronger than smoked marijuana's,
have a lower potential for abuse than the trace elements of THC in industrial hemp?
These and other characteristics of marijuana and Marinol contradict the assertion that
Unimed's proprietary substance has a lower potential for abuse relative to THC and
marijuana, Schedule I substances. As this finding would be required to support any change
in Marinol's Schedule II status, these legal and scientific findings present objections to
any rescheduling of Marinol that is inconsistent with the scheduling of marijuana, THC,
and nabilone. A hearing is requested in order to address these and other issues raised by
the relationship and scheduling of Marinol and other cannabinoids controlled by the CSA.
15) An additional objection to the rescheduling of Marinol involves US treaty
obligations regarding the control of THC. The US Court of Appeals has ruled that
determinations of US treaty obligations must not precede review of rescheduling petitions
by the DEA or by DHHS; indeed, DHHS evaluations may require amendment of international
treaties (NORML v. Ingersoll, 497 F2d at 658). However, this proposed rule for the DEA
explicitly states that a determination regarding US treaty obligations and the possible
rescheduling of Marinol was made prior to DEA review of Unimed's petition before its
referral to DHHS (63 FR 59751). A hearing is requested in order to submit this treaty
determination to public scrutiny and establish a record of public comment and the
independent evaluation of an administrative law judge. While the acceptability and
precedent of DEA's treaty determination regarding Marinol is clearly an issue to be
resolved by judicial review, the record and ruling produced in administrative hearings
will make a valuable contribution to such proceedings. Indeed, such hearings may provide a
remedy to DEA's deficient handling of this issue that may mitigate against eventual remand
by the Court of Appeals.
References:
Agurell, S., Hallden, M., et al. Pharmacokinetics and Metabolism of
D1-Tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacological
Reviews. Vol. 38, No 1. pp. 21 - 43. 1986.
ElSohly, Mahmoud, A.; Ross, Samir A. "Quarterly Report Potency Monitoring
Project." University, MS: Research Institute of Pharmaceutical Sciences. 1996.
Huestis, M., Sampson, A., et al. Characterization of the absorption phase of marijuana
smoking. Clin Pharmacol Ther. 1992, 52:31-41.
Letter of Edward Brandt, Jr. (DHHS) to Francis Mullen, Jr. (DEA) of August 16, 1982,
presentation of scientific and medical evaluation of tetrahydrocannabinol (THC),
notification of DHHS recommendation.
Letter of Edward Brandt, Jr. (DHHS) to Francis Mullen, Jr. (DEA) of May 13, 1983,
presentation of scientific and medical evaluation of marijuana plant material,
notification of DHHS recommendation.
Letter of Donald Ian Macdonald (DHHS) to John Lawn (DEA) of April 25, 1986,
presentation of scientific and medical evaluation of nabilone, notification of DHHS
recommendation.
Oviedo, A., Glowa, J, and Herkenham, M. "Chronic cannabinoid administration alters
cannabinoid receptor binding in rat brain: a quantitative autoradiographic study."
Brain Research, 616:293-302, 1993.
Physicians' Desk Reference, 47th Edition. Montvale, NJ: Medical Economics Data. 1993.
Rodriguez de Fonseca, F. et al. "Activation of Corticotropin-Releasing Factor in
the Limbic System During Cannabinoid Withdrawal." Science, Vol 276. June 27, 1998, pp
2050 - 2054.
Tanda, G. et al. "Cannabinoid and Heroin Activation of Mesolimbic Dopamine
Transmission by a Common Opioid Receptor Mechanism." Science. Vol 276 . June 27,
1997, pp 2048 - 2050.
United States Pharmacopeial Convention, Inc. Drug Information for Health Care
Professionals, Volume 1. Taunton, MA: Rand McNally. 1995.
(C) The following statement briefly states our position with regard to the objections
and issues above.
We are adversely affected, we believe, by:
(1) any action that reschedules one cannabinoid substance without consideration of
other cannabinoid substances.
(2) agency policies derived from determinations selectively withheld from public
comment and rulemaking procedures.
(3) agency determinations regarding scheduling of substances and treaty compliance
prior to DHHS reviews.
(4) scheduling substances in the most restrictive rather than the least restrictive
schedule allowed by law.
The rescheduling of Marinol into Schedule III is potentially unreasonable, arbitrary,
and capricious. It would be unreasonable to hold that the abuse potential of Marinol is
lower than that of THC in marijuana. It would be arbitrary to make a premature
determination regarding treaty compliance and obligations, and to schedule dronabinol
differently than THC with regard to its potential for abuse. It would be capricious to
accept such arbitrary and unreasonable findings that are self-serving to existing agency
policy and appear to benefit two privately held companies at the expense of the
criminalization of millions of individuals who use marijuana for medical and other
reasons.
We request a hearing to establish an evidentiary record regarding these issues and to
solicit the opinion and recommendation of an administrative law judge. We believe that
this hearing needs to evaluate evidence as to whether dronabinol satisfies the criteria
necessary for Schedule III status--particularly whether it has a lower potential for abuse
relative to Schedule I and II substances, and whether the proposed rescheduling of
dronabinol is consistent with treaty obligations.
Respectfully yours, Jon Gettman
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