Marijuana for Migraine Study Rejected by NIH, Revisited

Ethan Russo, M.D.


[posted March 1999 on MAPS website]

I regret that a second application to National Institutes of Health (NIH) in 1998 of the "Cannabis in Acute Migraine Treatment Project" has been rejected. MAPS has generously offered a forum for my views on this development. I will attempt to approach the issue objectively, but can not claim neutrality. Those readers who eschew a diet of "sour grapes" may wish to invest their time elsewhere. Background information is available in the following references: (Russo 1998; Russo et al. 1997).

In order to commence on a more illuminating note, I would like to offer the following analysis as evidence of why the migraine issue is important and deserves scientific investigation:

Many headache patients are seeking better treatments and are very open to "new ideas," for better or worse, even ones that are currently illegal. Migraineurs perceive themselves as significantly ill as demonstrated by unfavorable comparisons to other chronic conditions such as depression, heart disease, osteoarthritis and diabetes (Osterhaus et al. 1994; Solomon et al. 1993) Let us crunch a few numbers. Migraine afflicts 14% of females and 8% of males (Linet et al. 1989), for a composite of 11%. The cost of migraine to the U.S. economy is estimated at $5-17 billion annually. In total numbers, some 34.9 million people in the USA suffer moderate to severe migraine with attendant disability (Stewart et al. 1992). About 70% of people respond to subcutaneous administration of sumatriptan (Mathew 1997), the current "gold standard." About 30% fail, or an even greater number have sufficient side effects that they prefer not to use it. Multiplying 30% by 34.9 million, we arrive at a figure of about 10.5 million people in the USA alone that might surpass even these artificially rigorous criteria to employ smoked Cannabis to treat their migraines, whether symptomatically, or prophylactically. I feel the true figure is a good bit "higher."

The second Cannabis in Acute Migraine Treatment Project application was undertaken with full cognizance of previous criticisms from NIH, and incorporated a "double dummy" regimen as suggested by the 1997 NIH Consensus Panel on Medical Marijuana. The following is the study abstract as submitted:

Rationale: Cannabis, or marijuana, has been used for centuries for both symptomatic and prophylactic treatment of migraine. It was part of the Western pharmacopoeia for this indication even into the mid-twentieth century. Current anecdotal studies continue to refer to its efficacy for this malady, while biochemical studies of THC and anandamide have provided a scientific basis for such treatment.

Design: Forty adult patients meeting International Headache Society (IHS) criteria of acute migraine with or without aura, with headache frequency of three or more attacks per month, will be recruited. Exclusion criteria will include concomitant use of MAO inhibitor drugs, pregnancy, cardiac conditions, history of drug or analgesic dependency, or affliction with the chronic daily headache variant. A double-blind crossover study design will be pursued. All patients will undergo a detailed screening neurological examination. After suitable informed consent, study patients will be randomized to one of two groups. Group A patients will initially receive study medications consisting of Marinol (dronabinol, synthetic THC) 10 mg. p.o. plus smoke a placebo marijuana cigarette, or alternatively receive sumatriptan 6 mg. s.c. Group B patients will initially receive an oral placebo capsule resembling Marinol plus smoke a 4% THC content marijuana cigarette, or alternatively, sumatriptan 6 mg. s.c. The pyrolysed Cannabis dose will be titrated to the patients' responses. All patents will be monitored for one hour, at which time they will complete questionnaires regarding symptom-relief employing visual analogue scales. A Folstein Mini-Mental State Examination will also be performed. Blood samples for THC will be drawn at ten minutes and two hours except in those patients who received sumatriptan. Folstein tests and questionnaires will be repeated at the two, three and four hour-hour marks. At the end of three hours, any patient who desires additional symptomatic relief will be offered 1000 mg. of magnesium sulfate IV as a rescue medication. After four hours, patients will be allowed to return home, with a designated driver, or via arranged transportation. All patients will subsequently complete questionnaires at the twenty-four hour mark to determine efficacy of their treatment with respect to pain levels, nausea, photophobia, and their perceived ability to engage in work or study activities. Patients will be treated for up to 10 events per three-month block. After a two-week "washout period," groups A and B will crossover regimens. Other parameters of interest in the study will pertain to any rebound headache, the observed study medication side-effect profiles, including the patient's relative ability to function normally post treatment, and subsequent frequency of attacks. Results will be subjected to standard statistical analyses.

Prior to its submission, I sought and obtained approval of this study design by two major university deans of pharmacy and pharmacology, as well as that of a distinguished professor emeritus that served on the NIH Panel.
After the rejection of the 1997 protocol, I attempted a dialogue with an identified program official that was charged with the responsibility to "discuss your options and obtain advice." I will not embarrass this person by mentioning her name, inasmuch as I believe her to be under unyielding political pressure, although this was pointedly denied. Twice I sent her copies of the first protocol with my responses along with a plea for discussion and direction. None was forthcoming. E-mail follow-up correspondence went unanswered. The official later disavowed any memory of having received the information. Who, then, is opening the mail?
The response to my verbal request for direction after the second rejection was terse, "I can not write it for you." Who asked?

As was within my rights by NIH's own policy, the 1998 protocol was sent with the clear request that one or more members of the American Association for the Study of Headache (AASH) be invited to sit on the review panel. I supplied numerous suggestions of individuals who might assist in evaluation of the new protocol. After I obtained news verbally of the 1998 rejection, I discussed this with the "program official," which would not confirm or deny whether any of the suggested headache specialists had been recruited. The subsequent written critique included the composition of that panel. It contained twenty members. Cross-referencing the names against the rosters of AASH and the American Academy of Neurology (AAN) produced no matches. Closer inspection reveals that one is a Ph.D. in a neurology department, and another a psychiatrist in a conjoined department with neurology. However, none are American Academy of Neurology member neurologists, and none are headache specialists. Even if there had been one reviewer with specific expertise in migraine, the lack of response to my request strongly suggests overt political bias, and deliberate avoidance of the requested panel composition, as was within my rights by NIH policy.

Written critiques by three individuals were provided. The first indicated, "The significance of the proposed study is open to question. While there are clearly gaps in our knowledge regarding the potential therapeutic effect of marijuana in migraine, there is only an anecdotal evidence to suggest that marijuana may be helpful for the treatment of migraine headaches." This was a subsequently repeated refrain: "Anecdotal, Anecdotal, Anecdotal." I believe that label to be falsely applied. At the turn of the last century, George Santayana said, "Those who cannot remember the past are condemned to repeat it." (Santayana 1905-1906). In this instance, choosing to ignore thousands of years of human use of Cannabis and a century of mainstream Western pharmaceutical application for therapeutic purposes is a flagrant example of medical myopia. Using the pejorative term "anecdotal" as some reasonable excuse to preclude the scientific study of Cannabis is surely a political stance, and can not be defended as being concordant with the spirit of seeking higher knowledge. It is disingenuous to criticize a protocol for lacking components that have been prohibited. All our reports on efficacy of clinical Cannabis will remain ^"anecdotal" until the federal government allows its study. No, rather, government should be promoting Cannabis research, as their panel of experts recommended.

All reviewers had reservations about my "organization" and "lack of preliminary data." Once again, that "lack of data" has been due to a political barrier, and not to a dearth of scientific support for use of Cannabis in migraine treatment.
The NIH Consensus Panel made clear that pilot studies were not needed for Cannabis, but rather clinical study designs that included comparison to placebo and a standard pharmaceutical for the same indication. I indicated that policy suggestion in the protocol, but apparently it carried little weight with the reviewers.
One critic observed "this literature review is somewhat selective and does not reflect the more recent literature suggesting important cognitive impairments associated with sustained marijuana use." I was ^"selective" in this review in order to address pertinent clinical issues that might reasonably be encountered in the course of the clinical study. For every study that claims cognitive damage due to Cannabis, there are others of more compelling methodology that see little or none (Zimmer and Morgan 1997). Such dangers in the proposed protocol are nil, and that criticism irrelevant: acute mental status changes from Cannabis smoking are transient, and no study has ever shown compelling evidence of permanent cognitive changes after the sort of episodic use planned in this study protocol.

The second reviewer had the only nice comments, "The proposal is creative and a well-designed, systematic assessment on the effects of THC on migraine would add to the scientific literature." However, in the next paragraph, it is said, "Importantly, he does not appear to have experience in the design or conduct of clinical trials." It seems ironic that I could lack the experience of design, and yet formulate one that was "creative," even if it only aspired to being well designed! What is this person trying to say? Their criticism of my inexperience in clinical trials is equally undermined, and has no foundation in any event. It is truly difficult to join the ranks of the Good Old Boys.
This reviewer also indicated "the PI should consult with investigators who have more experience in running clinical trials." I did. They approved. Unfortunately, despite efforts to enlist "big guns," I was not successful in signing them on to the study itself. Perhaps they were more cognizant than I of the political impossibility of approval of this study by the powers that are aligned against it. Once again, the study's ability to attract test subjects was criticized despite a careful analysis designed to allay that concern.
It is my considered opinion that NIH will never approve this study in any form, and I will not apply for a third and last time in a vain attempt to wrest some Pyrrhic victory from the ashes of its defeat. Rather, I hope to take part in clinical studies of whole Cannabis extracts via an inhaler mechanism in migraine treatment organized by Dr. Geoffrey Guy in the UK (It is unlikely that smoked Cannabis trials will occur in that country). Dr. Guy has the good fortune to have full government backing for his investigations by a more progressive and compassionate government. Additionally, a group of researchers on the West Coast are attempting to mount clinical studies of Cannabis outside the jurisdiction of National Institute on Drug Abuse's (NIDA) stranglehold on its supply. At this moment in history, it is clear that the American people strongly support the provision of "medical marijuana." The politicians have failed to heed the mandate, and are pursuing their own agendas in a familiar dance of ignorance and neglect, to the eternal detriment of suffering patients.

Lest there remain defenders of the status quo that have managed to read this far, I would like to offer the following two excerpts from Alan Leshner, Ph.D., the Director of NIDA. The first is from a letter dated October 27, 1998 in response to my request for provision of Cannabis for clinical study, without NIH review:

If your project meets accepted standard of scientific design, qualifies for funding on the basis of peer review, and is funded by the NIH, NIDA will be able to provide marijuana cigarettes for you study.

Please contrast the above with an excerpt from a November 10, 1998 form letter sent by Dr. Leshner in response to an inquiry by a Congressman on behalf of his constituent in Oregon:

You should be aware that it has been and will continue to be NIDA policy to supply cannabis to scientifically meritorious studies regardless of whether or not their funding comes from NIH.

Am I the only one that interprets these statements as mutually exclusive? The fact is that NIDA has not in recent memory supplied any clinical study with Cannabis except after NIH approval. The single instance of NIH acquiescence is Donald Abrams' study of Cannabis in AIDS wasting syndrome. That approval only came after the basic study design was changed from an efficacy study (one assessing the proposition that Cannabis affects weight gain in patients with AIDS wasting), to a safety study (one testing primarily whether Cannabis poses immunological risks to HIV patients on protease-inhibitor drugs). Despite common knowledge in the populace of the benefits of Cannabis for this indication, and its broad public support, Dr. Abrams' study required 5 years to gain approval!

If tomorrow I were to apply to NIDA under an assumed name to demonstrate some harmful effect of Cannabis, I have little illusion that the material would be provided to me without the obligatory Byzantine process of NIH approval and funding. Hypocrisy, Hypocrisy, Hypocrisy.

Migraine as a medical problem is compelling by any measure. I will continue to pursue the clinical investigation of Cannabis in migraine and other medical indications vigorously in spite of this temporary setback.

Ethan Russo, MD

REFERENCES:

Linet, M.S., Stewart, W.F., Celentano, D.D., Ziegler, D. and Sprecher, M., An epidemiologic study of headache among adolescents and young adults, JAMA, 261 (1989) 2211-6.

Mathew, N.T., Serotonin 1D (5-HT1D) agonists and other agents in acute migraine, Neurol Clin, 15 (1997) 61-83.

Osterhaus, J.T., Townsend, R.J., Gandek, B. and Ware, J.E., Jr., Measuring the functional status and well-being of patients with migraine headache, Headache, 34 (1994) 337-43.

Russo, E., Cannabis for migraine treatment: the once and future prescription? An historical and scientific review, Pain, 76 (1998) 3-8.

Russo, E.B., Medora, R., Parker, K. and Thompson, C., Schedule 1 Research Protocol: An Investigation of Psychedelic Plants and Compounds for Activity in Serotonin Receptor Assays for Headache Treatment and Prophylaxis, Bulletin of the Multidisciplinary Association for Psychedelic Studies, 7 (1997) 4-8.

Santayana, G., The Life of Reason, 1905-1906.

Solomon, G.D., Skobieranda, F.G. and Gragg, L.A., Quality of life and well-being of headache patients: measurement by the medical outcomes study instrument, Headache, 33 (1993) 351-8.

Stewart, W.F., Lipton, R.B., Celentano, D.D. and Reed, M.L., Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors, JAMA, 267 (1992) 64-9.

Zimmer, L.E. and Morgan, J.P., Marijuana myths, marijuana facts : a review of the scientific evidence, Lindesmith Center, New York, 1997, xv, 241 pp.

Ethan B. Russo, M.D.
Department of Neurosciences
Western Montana Clinic
515 West Front Street
Missoula, MT 59807-7609
USA

Voice: (406)329-7238 -- E-Mail: ptm5739@montana.com

Web site: Plants of the Machiguenga: http://www.montana.com/manu


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