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