The Making of Marinol
Medical Marijuana Memory Blog #41
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The possible reclassification of cannabis is in the news a lot. The battle to move cannabis out of Schedule I — the most restrictive of five schedules —has been raging since 1972, when the National Organization for the Reform of Marijuana Laws —NORML— first petitioned the Bureau of Narcotics and Dangerous Drugs (now the Drug Enforcement Administration) to reschedule marijuana based on its long history of medical use. We’ll return to that epic struggle in just a moment.
Fifty years later, in 2022, the president of the United States, Joe Biden, said the classification of marijuana in Schedule I “Makes no sense” and asked that the Department of Health and Human Services take a look at things. They did and suggested to the DEA that marijuana should be moved to Schedule III, where it would join the synthetic version of its most psychoactive ingredient, delta-9 THC, known by its pharmaceutical name as dronabinol. Under its brand name, Marinol, this synthetic has been available by prescription for 40 years. The story of how Marinol became an FDA-approved medication while cannabis and the natural form of delta-9 THC continue to languish in Schedule I is an interesting one that I started in my previous blog, #40 Neal-ing to Synthetics.
Searching for the ‘pot pill’
That blog tells the story of how the federal government agencies were forced, in the late 1970s and early 1980s, to respond to the medical marijuana movement and its demand for legal access to federal supplies of natural cannabis. To summarize, in the early years of the medical marijuana movement, federal officials were slow to respond because they were certain that a drug produced by Eli Lilly, Nabilone, would undermine the movement’s momentum. When Nabilone crashed and burned, federal bureaucrats had to scramble to respond to the loud demands of patients, particularly cancer patients, to release marijuana for medical use. The bureaucrats opted to release the synthetic form of delta-9 THC instead, which had been developed for research purposes and was never intended for therapeutic applications. Calling this synthetic molecule, mixed in sesame oil, a “pot pill”, the government effectively convinced a naive public that it was receiving a better form of cannabis.
But there was a problem. Initially, the delta-9 THC pills had a limited release to the public via the Group C program at the National Cancer Institute (NCI), but this was not a long-term solution. It was inappropriate for NCI to produce the THC pills indefinitely, and, to its credit, NCI just said “no” to what I feel certain was intense pressure from DEA and FDA to continue the status quo. Therefore, the government was compelled to find a pharmaceutical company willing to assume the responsibility for producing dronabinol and initiated discussions with various pharmaceutical companies.
Oh, to be a fly on the wall during those negotiations! FDA had first approached the major pharmaceutical companies, all of which declined. It finally convinced a small New Jersey company, Unimed, to take on the task of moving delta-9 THC to the market by filing a New Drug Application (NDA), the final step in the drug approval process in the U.S.
Unimed signed on sometime around 1981 and no doubt thought the NDA would be a walk in the park. But it would be four years before the FDA approved Unimed’s NDA for dronabinol. It is probably fair to surmise that part of that delay was due to scheduling matters. Dronabinol, after all, was delta-9 THC, and delta-9 THC was a Schedule I drug, like its progenitor, marijuana. If dronabinol were to be released publicly, it would need to be rescheduled for medical use.
The tortured path of the first petition to reschedule
And here is where that 1972 NORML petition comes in. To say the petition was stonewalled, first by BNDD and then the DEA, is an understatement. For several years, the petition was simply ignored, so NORML went to Court for the first time and argued that the law required the government to respond. The Court agreed. So, the DEA wrote a letter to NORML, essentially stating “Denied”. NORML returned to Court, arguing that the DEA was being frivolous and requested a thorough review. The Court agreed and ordered the DEA to do so. This time, the DEA sent several pages of a purported review and denied the petition. NORML went back to Court and …well, you get the picture. These see-saw actions had been ongoing for more than a decade when the question of what to do about dronabinol emerged. At this point, DEA came to NORML with an offer: if NORML didn’t fight the rescheduling of dronabinol, then DEA would hold hearings on the medical utility of marijuana. It was completely disingenuous, as the DEA was, at that time, under a court order from the Court of Appeals to hold hearings on the NORML petition.
NORML’s executive director at the time was Kevin Zeese, a practical and skilled lawyer who recognized this as an opportunity that wouldn’t come again. The promised hearings would be held before the Chief Administrative Law Judge for the DEA. They would take place in several major cities throughout the country, thereby maximizing the potential for witnesses to come forward. With 34 state laws on the books that recognized the medical utility of cannabis and a mobilized medical marijuana movement, Zeese realized this was THE opportunity for the petition to succeed. He got in touch with Robert Randall and asked if the Alliance for Cannabis Therapeutics (ACT) would be willing to come on board. Zeese then sweetened the deal and said that if ACT’s pro bono law firm, Steptoe & Johnson, would agree to participate, NORML would take the second seat and allow ACT to be the lead petitioner. Zeese would take some heat for these moves. Many activists thought NORML should hold DEA’s feet to the fire and cause a ruckus about rescheduling dronabinol, but not marijuana. But Zeese’s steps were masterful. With NORML agreeing to let ACT take the lead, Steptoe & Johnson felt comfortable about committing massive resources to the hearings. The result was the most comprehensive hearings on medical marijuana in the 20th century and Judge Young’s famous decision in favor of rescheduling. Those hearings are the topic for a future Medical Marijuana Memory Blog.
Drug of abuse?
With the fear of being challenged removed, the DEA took steps in 1985 to reschedule dronabinol, now named Marinol. Initially, dronabinol was classified as a Schedule II drug. The DEA was confident that druggies would chase this “high abuse potential” drug, but 13 years later, a 1998 article in the Journal of Psychoactive Drugs (Calhoun, et.al) reported on a study that found dronabinol to be quite a bit milder than first proposed. They wrote:
Healthcare professionals have detected no indication of "scrip-chasing" or "doctor-shopping" among the patients for whom they have prescribed dronabinol. Cannabis-dependent populations, such as those treated in our Clinic and seen by the addiction medicine specialists we interviewed, have demonstrated no interest in abuse of dronabinol. There is no street market for dronabinol, and no evidence of any diversion of dronabinol for sale as a street drug. Furthermore, dronabinol does not provide effects that are considered desirable in a drug of abuse. The onset of action is slow and gradual, it is at most only weakly reinforcing, and the overwhelming majority of reports of users indicate that its effects are dysphoric and unappealing. This profile of effects gives dronabinol a very low abuse potential.
These facts were evident to anyone in the 1980s who cared to pay attention to patient reports and the results of those few states that had been able to navigate the ridiculously torturous route to research with natural cannabis and delta-9 THC. In 2002, the DEA was forced, by litigation, to reschedule Marinol to Schedule III, where it resides today. Some argue that it could easily be moved to Schedule V, but I’m not holding my breath.
Observers of the current effort to reschedule the plant will note that the FDA and DHHS have recommended to the DEA that cannabis, and presumably all of its ingredients, be moved to Schedule III. In the long history of attempts to reschedule cannabis, this is at least some progress. But I would caution today’s activists to be realistic about the chances of marijuana being rescheduled as long as the DEA has final say in scheduling matters. In all of the thousands of words that have been written about cannabis rescheduling, the ones I yearn to see are those that call for an end to the DEA’s power in determining a drug’s “abuse potential”. To place this decision in the hands of police and lawyers makes no sense whatsoever except to demonstrate the agency’s distrust of science that dates back to Harry Anslinger and the 1930s. Abuse is an arbitrary measuring stick, and allowing the DEA to determine abuse places too much power in an agency that is, in theory, chiefly focused on crime. If the scientists at the FDA and DHHS have concluded that cannabis should be in Schedule III, then that is where it should be. Their letter to the DEA should be an order, not a recommendation.
Alas, I have seen no such call. In the best of worlds, the DEA would be abolished and reorganized, with perhaps an extensive burning of sage plants to rid the agency of the many ghosts of prohibition that seem to occupy its policies and performance.
A final word on Marinol. I’m glad it was approved for marketing in 1985, although it was steered there by hands too heavily influenced by abuse philosophy and not therapeutic application. Pills of 10mg were the norm to start with. Remember, this is the most psychoactive ingredient in marijuana. There were also 5mg and 2.5mg dose pills, although even those may be too strong. Several years ago, I attended a conference in Europe where a German pediatrician raved about Marinol. He found it to be among the best medicines for his young cancer patients. But this doctor didn’t give pills. His facility obtains Marinol in bulk, and the hospital pharmacy compounding department prepares an IV solution with the quantity of Marinol determined by the patient's weight. This is the classic cannabis therapeutic mantra: start low, go slow, and, like so many, he has determined that less is more. His words were inspiring and offered direction to anyone who took the time to listen, but I doubt there was a DEA representative in the hall. ❖
Reference:
Calhoun, S. R., Galloway, G. P., & Smith, D. E. (1998). Abuse Potential of Dronabinol (Marinol®). Journal of Psychoactive Drugs, 30(2), 187–196. https://doi.org/10.1080/02791072.1998.10399689