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.
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
The second reviewer had the only nice comments, "The proposal is creative
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
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
any event. It is truly difficult to join the ranks of the Good Old Boys.
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
Ethan B. Russo, M.D.
Voice: (406)329-7238 -- E-Mail: firstname.lastname@example.org
Web site: Plants of the Machiguenga: http://www.montana.com/manu
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