Principal Investigator: Ethan Russo, M.D.
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DESCRIPTION Rationale Design 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. PERFORMANCE SITE(S) (organization, city, state) KEY PERSONNEL. See instructions on Page 11. Use continuation pages as needed to provide the required information in the format shown below. Name Organization Role on Project PHS 398 (Rev. 5/95) TABLE OF CONTENTS
Page Numbers Face Page 1 *Type density and size must conform to limits provided in Specific Instructions on page 6. Appendix is included Appendix (Five collated sets. No page numbering necessary for Appendix) Number of publications and manuscripts accepted or submitted for publication (Not to exceed 10) Other items (list): Ethan Russo -- Selected Publications Russo, E.B., "To Know Them as People," chapter in Mariska, J.A. & van den Pol (Eds.), R., Changes of Necessity, Changes of Choice, Brookline Books, Cambridge, MA, 1993. Russo, E.B., An Ocelot for a Pillow: Researching Headaches, Hallucinogens, and Hunting Magic Among the Machiguenga in Man?, non-fiction book (inedit) Russo, E.B., The Last Sorcerer: Echoes of the Rainforest, fiction book, accepted for publication, Inner Traditions International, Rochester, VT, 1997. Russo, E.B., Medora, R., Parker, K.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," Bull. of Multidisc. Assoc. for Psyched. Stud. 7(1):4-8, 1997. Weber, J.T., O'Connor, M-F, Hayakataka, K., Colson, N., Medora, R., Russo, E.B., and Parker, K.K., "Activity of Parthenolide at 5HT2A Receptors," Journal of Natl. Prod. 60:651-653, 1997. Russo, E.B., "Cannabis for Migraine Treatment: The Once and Future Prescription: An Historical and Scientific Review with Suggestions for Subsequent Studies," Pain 76(1):3-8, 1998.
Serotonin receptor pharmacology studies on approximately 100 species of medicinal plants collected in Parque Nacional del Manu, Peru, and Belize, with and the above team. Biochemistry of neotropical gesneriads with reported ethnobotanical uses for headache or psychoactive effects, supported by the American Gloxinia and Gesneriad Society ($1500), with the above team. Clinical studies on aromatherapy treatment of migraine in process.
Dr. Russo has served as an article reviewer for the journal Headache, scientific advisor for Shaman Pharmaceuticals, and medical consultant on herbal treatments for various magazine articles and books. He is former director of the Western Montana Muscular Dystrophy Association Clinic. He was an expert witness in fourteen cases for the Vaccine Injury Compensation program, Department of Health and Human Services, Washington, D.C. Additionally he has served for several years on the Ethics Committee of St Patrick Hospital, Missoula, MT. He is the author of several papers, two books, one of which is due to be released in 1999. Dr. Russo will be principal investigator, and oversee day-to-day operation of this project. He will direct publicity and patient recruitment for the study, approve or disapprove prospective study subjects, oversee study drug administration, and troubleshoot patient clinical problems. He will also chair team meetings, supervise data analysis, and preparation of potential publications from the resulting data. Dr. Russo will also administer the grant. A 30% salary support is requested for Dr. Russo for two months of patient recruitment, six and a half months of drug study trials, and one month of data analysis. Jeannine Mielke (Research Assistant): Ms. Mielke is a doctoral candidate in psychology at the University of Montana, and psychometrician at the Western Montana Clinic. She will be responsible for subject recruitment, confirmation of eligibility, assistance in obtaining informed consent, enrollment of subjects, collection of subject data, data management, statistical generation and preparation of study results. We are requesting 25% salary support for 9 months for Ms. Mielke = $3600. Laura Taylor Painter (Research Assistant): Ms. Painter is a doctoral candidate in psychology at the University of Montana, and psychometrician at the Western Montana Clinic. She will be responsible for subject recruitment, confirmation of eligibility, assistance in obtaining informed consent, enrollment of subjects, collection of subject data, data management, statistical generation and preparation of study results. We are requesting 25% salary support for 9 months for Ms. Painter = $3600. Stuart Hall, Ph.D.: Dr. Hall is an Associate Professor in the Department
of Psychology at the University of Montana. His area of expertise is
clinical neuropsychology and he has extensive training in physiological
psychology. He is a member of both the clinical and experimental faculty.
Dr. Hall will provide consultation on methodology, clinical measures,
data collection, and data interpretation. He will supervise research
assistants conducting clinical assessments of subjects and will assist
in the preparation of abstracts and manuscripts reporting the results
of the study. We are requesting 5% salary support for Dr. Hall. Brian Steele, Ph.D.: Brian M. Steele, Ph.D. (Consultant): Dr. Steele is a Visiting Assistant Professor of Mathematics at the University of Montana, Missoula. He is an expert on the statistical analysis of longitudinal studies and related statistical designs. His Ph.D. dissertation developed an improved approach to estimation for generalized linear mixed models, a large class of statistical models that includes the Pilot Study design as a prototype. Recently, he has developed a previously unavailable general approach to hypothesis testing under the generalized linear mixed model. He has been a statistical consultant for the past ten years, working primarily on problems arising in biology and ecology. He has published several papers on design and analysis of longitudinal monitoring studies. Dr. Steele has been a Professor at University of Montana for two years and has been course coordinator of both the Linear Mathematics and Introductory Statistics courses, positions that demand extensive planning and supervision of teaching assistants. Dr. Steele will assist researchers to insure that the study yields statistically valid data. He will be responsible for the statistical analysis and interpretation of the study results and he will be responsible for the statistical content of abstracts and manuscripts reporting the findings of the study. We are requesting 33% salary support for Dr. Steele for 3 months: $4133 + $783 fringe = $4916. Study Nurses: Two RNs will be hired for this position for a projected two months of patient recruitment, the six and one half months of patient drug trials, and one month of data analysis. They will assist in patient enrollment, administration of study medication, and administration of tests. They will also perform venipunctures for the THC assays, and magnesium sulfate administration. They will monitor study patients, and assess side effects, and assist in follow-up. Two prospective candidates have been interviewed and have expressed interest in the position. 100% salary support is requested for this position for the 9 month period: $16/hr. + 15% fringe = $29,440 x 2 = $58,880. Consultant Costs Equipment D. Travel Airfare to New York: $600 (government rate) Patient Care Costs Other Expenses Funds are requested to purchase sumatriptan for the 40 subjects. Each would receive up to 10 injections during the study, incurring costs of: 400 injections x $25/ injection = $10,000. In the course of the study, the 40 subjects may require up to 5 trials each of Cannabis. Therefore, 200 marijuana cigarettes of 4% THC content are requested. In the course of the study, the 40 subjects may require up to 5 trials each of placebo Cannabis. Therefore, 200 placebo cigarettes of 0% THC content are requested from NIDA. 200 placebo capsules resembling Marinol are requested from NIDA or the manufacturer: cost unknown. Costs are requested for an estimated 30% of total patient trials where supplemental magnesium sulfate is needed: 800 trials x 0.3 = 240 doses x $10/ treatment = $2400. A small number of sumatriptan inhalers may be needed for study patients intolerant of, but not truly allergic to sumatriptan injections. Clinical Laboratory Costs: Additionally, venipuncture costs are $4 x 400 x 2 = $3200. Shipping of samples: $15 x 400 (or less if batched) = $6000.
Reimbursement is requested for taxi service for study subjects who are unable to provide the requested designated driver. Hopefully, this will be required in no more that 25% of instances: 40 subjects x 20 sessions x $10 taxi fare x 2 ways x 0.25 = $4000. Funds are requested for 2 ventilation fans, and 4 bean bag chairs for patients: 6 x $60/piece = $360. Funds are requested for room rent from St. Patrick Hospital: $ 225/month x 10 months x 2 rooms = $4500. Funds are requested for a telephone for the study room: $ 25/month x 10 months = $250. Funds are requested for postage: $0.32 x 12 mailings/patient x 40 patients + $0.32 x 200 for recruitment to area physicians = $218. Funds are requested for advertisements in local newspapers to aid in recruitment of study subjects: $200/ad to run 3 occasions = $600 3 alpha-numeric pagers and 3 cellular telephones are requested for study use for 10 months: (3 x $20/mo. x 10) + (3 x $24.44/mo. x 10) = $1332. Funds are requested for a safe to contain sensitive study materials, such as patient files and study medications = $1000. Funds are requested for the Investigational Funds are requested for a scale to weigh unused portions of marijuana and placebo marijuana cigarettes = $1200. No indirect costs will be associated with this study, inasmuch as Dr. Russo will administer it. Russo, Ethan ACTIVE The goal of this grant is to study serotonin receptor activity of neotropical gesneriads with reported psychoactive effects or use in headache treatment. Overlap: 0% Multidisciplinary Association for Psychedelic Studies Overlap: 0% 3) Multidisciplinary Association for Psychedelic Studies Overlap: 100%
ACTIVE The major goal of this study is to determine if measuring response latency on two standard neuropsychological tests will significantly contribute to the ability to identify individuals who are malingering on these tests. OVERLAP
RESEARCH PLAN Introduction to Revised Application: This application has been substantially revised, and in the case of
the study protocol, totally so.
Hypothesis 1: Pyrolysed Cannabis may ameliorate the pain and nausea associated with migraine. Hypothesis 2: Oral dronabinol may also show efficacy in this regard, but to a lesser degree, and with a slower response than smoking Cannabis. A secondary goal is to assess whether periodic use of THC products in the study group alters the frequency or severity of migraine attacks. Hypothesis 3: THC use may exert a prophylactic effect in migraine. Rationale: If the current pilot study demonstrates therapeutic efficacy of dronabinol or smoked Cannabis in acute migraine treatment, with attendant safety, additional in-depth, long-range studies may be warranted. B. Background and Significance Note: An abbreviated version of this discussion is available in: Russo,
E.B., "Cannabis for Migraine Treatment: The Once and Future Prescription?:
An Historical and Scientific Review," Pain 76(1):3-8, 1998 (Appendix). By the fifteenth century B.C. the Chinese book known as the Rh-Ya was compiled, and in it there is mention of the herb Ma, the Cannabis sativa plant. Not only were the fibers and potent resins employed at this time, but the Rh-Ya describes the first ritualistic or shamanistic use of the plant. The Atharva Veda of India, dated to between 1400 and 2000 B.C.E. referred to a sacred grass, bhang, and medicinal references to Cannabis were cited by Susrata in the sixth to seventh centuries (Chopra & Chopra, 1957). One author (Dwarakanath, 1965), noted Ayurvedic preparations called Rasachandrika vati and Mahalakshmivilasa rasa, said to contain Cannabis, indicated for: Diseases of the head including neuralgic headaches, haemicrainia etc. (Shiroaroga [term for migraine]) Although many authorities have cited an absence of Cannabis in Ancient Egypt, Nunn (1996) cited no less than five supporting experts that it was employed in fact (Mannische, 1989; Ghalioungui, 1987; Charpentier, 1981; Faulkner, 1962; Dawson, 1934): There is general agreement with the view of Dawson that shemshemet means cannabis, and the identification was strongly supported by the use of hemp in rope making. As a drug, it has remained in active use ever since pharaonic times. It does not appear very often in the medical papyri, but it was administered by mouth, rectum, vagina, bandaged to the skin, applied to the eyes and by fumigation. Mannische (1989) also has cited evidence of Cannabis use in Ancient
Egypt in the Pyramid Texts of the mid 3rd millenium B.C.E. Physical
proof includes discoveries of hemp remnants in the tomb of Akhenaten
(Amenophis IV) around 1350 B.C.E., and Cannabis pollen in the tomb of
Rameses II, who died in 1224 B.C.E. Both in the original Hebrew text of the Old Testament and in the Aramaic translation, the word kaneh or keneh is used either alone or linked to the adjective bosm in Hebrew and busma in Aramaic, meaning aromatic. It is cana in Sanskrit, qunnabu in Assyrian, kenab in Persian, kannab in Arabic and kanbun in Chaldean. In Exodus 30:23, God directs Moses to make a holy oil composed of "myrrh, sweet cinnamon, kaneh bosm and kassia." In many ancient languages, including Hebrew, the root kan has a double meaning ñ both hemp and reed. Current estimates posit the writing of Exodus to between 900-600 B.C.E.,
while referring to much earlier events. Although the issue of its use
in the Bible has been hotly debated, physical evidence of medicinal
Cannabis use in Israel/Palestine was recently discovered (Zlas et al.,
1993). In a burial tomb in Beit Shemesh (midway between Jerusalem and
Tel Aviv), the skeleton of a 14 year old girl was found along with 4th
century bronze coins. Contained in her pelvic area was the skeleton
of a term fetus, of sufficient size to disallow a successful vaginal
delivery. In her abdominal area, gray carbonized material was noted
and analyzed, yielding TLC and NMR spectroscopy evidence of delta-6-
tetrahydrocannabinol, a stable component of Cannabis. The authors stated: They further remarked that Cannabis retained an indication as an aid
to parturition into the 19th century, as above noted. - for when they have parties and sit round a fire, they throw some of it into the flames, and as it burns it smokes like incense, and the smell of it makes them drunk just as wine does us; and they get more and more intoxicated as more fruit is thrown on, until they jump up and start dancing and singing. Physical evidence of Scythian use of Cannabis has been unearthed (Rudenko, 1970; Artamonov, 1965). The "Frozen Tombs" of Pazyryk, dated to the 5th to 3rd centuries B.C.E., were excavated earlier this century in the Altai Mountains, south of modern-day Novosibirsk near the Mongolian and Chinese borders. Artamonov (1965) describes: One particularly interesting apparatus was a kind of cone-shaped miniature tent, covered with a felt or leather rug, standing over a copper censer. Hemp seeds found on the spot suggest that this contrivance was a special enclosure that could be filled with narcotic smoke from the burning seeds. Rudenko (1970) also described a leather flask containing hemp seeds, and asserted: Here it will be merely remarked that smoking hemp, like smoking hashish, took place without a doubt not just as a ceremony of purification after burial but in ordinary life; hashish was used as a narcotic. In the 1st century, Diosocorides published his Materia Medica, perhaps
the first pharmacopoeia in the Western World. He described the plant
and its analgesic role (Dioscorides, 1968): In the 2nd century, the Greek physician Galen expounded on medical indications, mainly gastrointestinal (Brunner, 1977), but also noted of Cannabis (Galen): If consumed in large amounts, it affects the head by sending to it a warm and toxic vapor. Medicinal use in the classical world extended in to the early Middle
Ages through Paulus Aeginata (Paul of Aegina) in his 7th century Epitome,
wherein Cannabis was employed as a carminative (Lewis et al., 1971). The decoction of the root allays inflammations of the head, or any other parts; the herb or the distilled water of it, does the same. In 1712, Engelbert Kaempfer published his Amoenitatum Exoticarum Politico-
Physico-Medicarum,
in which he described the psychogenic effects of Cannabis as employed
in Persia and India (Dolan, 1971; Kaempfer, 1996). Also in 1874, a popular textbook, Practical Therapeutics stated (Waring, 1874): Of a good extract, gr. 1/4 to gr. ?, rarely gr. j, in the form of pill, is very effective in some forms of neuralgia, particularly -Migraina. Even in the severest and most intractable forms it often palliates greatly. It should be given every night, whether there be pain or not. These claims support both acute and prophylactic indications of Cannabis
for migraine. Another British physician agreed with the indication of Cannabis for headache (Fox, 1897): I understand by migraine a periodical nerve storm ñ- For the relief of the paroxysms antipyrin and phenacetin have often been in my experience successful. ñ- But I am accustomed to rely much upon cannabis indica, having had a pretty large experience of this remedy. The extract, often combined with cascara sagrada [Rhamnus purshianus DC Rhamnaceae], has controlled many, if not most, cases of migraine. In the same year the following blurb was attributed to "G.O.M." under the heading, "Letter From London (From Our Own Correspondent)" (Mackenzie, 1887): Dr. Stephen Mackenzie says that in doses of one-half grain Indian hemp, night and morning, and continued some time, is the most valuable remedy he has met with in the treatment of persistent headache. A doctor in India wrote of Cannabis indica (McConnell, 1888), and how proper storage was key to therapeutic response: Where care is taken in this respect, the therapeutic value of the drug in certain affections of the nervous system- tetanus, neuralgia, migraine - has been repeatedly recorded by competent observers, and its employment for the relief of such affections is well understood and more or less extensively resorted to. Dr. William Gowers is now considered one of the founding fathers of modern neurology. For treatment of migraine, he wrote (Gowers, 1888): Most relief is afforded to the pain by a good dose (thirty or forty grains) of bromide, and its effect is increased by the addition of five or ten minims of tincture of Indian hemp. For treatment of "headache," he stated: Sedatives are very uncertain in their influence. Opium and morphia are seldom useful, and often do more harm than good, in consequence of the indirect effect of the constipation that is produced. Gelsemium and Indian hemp frequently lessen the pain, the former chiefly in neuralgic forms about the front of the head, the latter not only in neuralgic, but in anaemic, and also other ill-defined forms of headache. The next year, a treatise was written on the use of rectal preparations of Cannabis (Farlow, 1889): Cannabis has few equals in its power over nervous headaches such as women with pelvic troubles are subject to. The Lancet published an article on Cannabis indica by J. Russell Reynolds,
personal physician to Queen Victoria (Russell, 1890) which stated: In relation to its use in headache, Reynolds said: Migraine: Very many victims of this malady have for years kept their suffering in abeyance by taking hemp at the moment of threatening, or onset of the attack. In the following year, the British Medical Journal published a short report, "On the Therapeutic Value of Indian Hemp" (Suckling, 1891), which stated: In migraine the drug is also of great value; a pill containing º gr. Of the extract with or without a º gr. of phosphide of zinc will often immediately check an attack, and if the pill will be given twice a day continuously the severity and frequency of the attacks are often much diminished. I have met with patients who have been incapacitated for work from the frequency of the attacks, and who have been enabled by the use of Indian hemp to resume their employment. In A Text-Book of Materia Medica and Therapeutics (Cowperthwaite, 1891),
once more, Cannabis indica was indicated for migraine treatment. -its most important use is in that opprobium of the healing art- migraine. Drawing subsequently from his own experience, Mattison stated: Failure with hemp is largely due to inferior preparations Cannabis in its various forms remained the focus of intense scrutiny, and continued to have its critics. Because of concerns of its dangers, the British and colonial authorities in India organized a study of all aspects of the issue (Indian Hemp Drugs Commission, 1893-1894). Its findings after exhaustive investigation and testimony exceeded 3000 pages, and were summarized as follows (Abel, 1980): (1) Moderate use of cannabis drugs had no appreciable physical effects on the body. As with all drugs, excessive use could weaken the body and render it more susceptible to diseases. Such circumstances were not peculiar to cannabis, however. (2) Moderate use of cannabis drugs had no adverse effect on the brain, except possibly for individuals predisposed to act abnormally. Excessive use, on the other hand, could lead to mental instability and ultimately to insanity in individuals predisposed by heredity to mental disorders. (3) Moderate use of cannabis drugs had no adverse influence on morality. Excessive usage, however, could result in moral degradation. Although in certain rare cases cannabis intoxication could result in violence, such cases were few and far between. The commission subsequently dissuaded any governmental suppression
of usage of Cannabis drugs. Not poisonous according to best authorities, though formerly so regarded. Antispasmodic, analgesic, anesthetic, narcotic, aphrodisiac. Specially recommended in spasmodic and painful affections; for preventing rather than arresting migraine; In 1900, a brief report on Cannabis indica appeared (Lewis, 1900), which stated, in part: In migraine, hemicrania, neuralgias, and headache due to eye-strain, it may be used with marked success A textbook of the era (Marshall, 1905) indicated that Indian hemp had been supplanted by other medicines for some indications, but: It appears, however, to be useful in headache of a dull continuous character. The extract in the form of pills is usually administered. As late as 1915, Sir William Osler, the acknowledged father of modern medicine stated of migraine treatment (Osler, 1915): Cannabis indica is probably the most satisfactory remedy. Seguin recommends a prolonged course of the drug. This statement once more supports its use for both acute and prophylactic
treatment of migraine. In cases where immediate effect is desired, the drug should be smoked,
the fumes being drawn through water. In fits of depression, mental fatigue,
nervous headache, feelings of fatigue disappear and the subject is able
to continue his work refreshed and soothed. Cannabis is used in medicine to relieve pain, to encourage sleep, and to soothe restlessness. -For its analgesic action it is used especially in pains of neuralgic origin, such as migraine, but is occasionally of service in other types. In the German literature, Cannabis use by extract or smoking was held
to be an "outstanding agent" (Dinand, 1921). In true migraine with hemianopsia this treatment is often most effectual in aborting the attack. The prevention of further attack is to be attained by the use of smaller amounts of the cannabis during the intervals -ñ In the years that followed, Cannabis came to be perceived as a drug
of abuse, smoked by certain classes of people as "marijuana"
or "marihuana." In an article entitled "The Weed of Insanity"
(Bragman, 1925), the author admitted, "It has some value in the
relief of migraine." Cannabis indica is sometimes very useful, when a reliable preparation can be secured. -Morphin should never be employed, except as a last resort. Despite its political downturn in popularity, a 1933 review of therapeutic
techniques (Fantus, 1933) recommended "fluidextract of cannabis": There is positively no evidence to indicate the abuse of cannabis as a medicinal agent or to show that its medicinal use is leading to the development of cannabis addiction. Cannabis at the present time is slightly used for medicinal purposes, but it would seem worth while to maintain its status as a medicinal agent for such purposes as it now has. There is a possibility that a restudy of the drug by modern means may show other advantages to be derived from its medicinal use. Despite this political event, in 1938 Robert Walton published a comprehensive review of Cannabis, with botanical, historical, chemical and political discussions (Walton, 1938). After discussing the issues of its abuse, and consequent legislation, he stated: More stringent regulations making the drug unavailable for medical and scientific purposes would be unwise, since other uses may be developed for the drug which will completely overshadow its disadvantages. The drug has certain remarkable properties and if its chemical structure were determined and synthetic variations developed, some of these might prove to be valuable, both as therapeutic agents and as experimental tools. In 1941, Cannabis preparations were dropped from the United States Pharmacopoeia (U.S.P.), but the following year, the editor of the Journal of the American Medical Association still advocated oral preparations of Cannabis in treatment of menstrual (catamenial) migraine (Fishbein, 1942): In this instance the patient may be given either sodium bromide or fluidextract of cannabis three days before the onset of the menstrual period, continued until three days after the menstrual period. As a seeming afterthought, he added: Ergotamine tartrate may also be given. The latter medicine remains in the migraine armamentarium, fifty-six
years later, but he considered it inferior to Cannabis. The practice of smoking marihuana does not lead to addiction in the
medical sense of the word. Despite political issues in the U.S.A., medical use of Cannabis continued
elsewhere. In 1947, an ethereal extract of Cannabis was still employed
for migraine treatment in Argentina (Kabel"k, Kreje" &
Santavy, 1960). Cannabis was still recommended as a homeopathic remedy
for migraine in 1956 in then East Germany (Auster & Schafer, 1956).
Everywhere it is considered to be of analgesic value, comparable to the opium derivatives. Moreover, it can be added to any relaxant to reinforce its action. Cooked leaves, which have been dried in the sun, are used in quantities of several grams per bowl of water. This decoction helps especially to combat migraines and stiffness; taken before sleep and before meals, it relaxes the nerves. Analgesic effects of Cannabis have retained importance in the folk
medicine of North Africa (Boulos, 1983). The concentrated resin exudate - is considered valuable in preventing and curing sick-headaches, neuralgias and migraine The following year, in a treatise entitled Indigenous Drugs of India (Chopra et al., 1958) the authors stated: Cannabis is used in medicine to relieve pain, to encourage sleep, and
to soothe restlessness. There is little definite knowledge of the therapeutic
effects produced, but in some persons it appears to produce euphoria
and will often relieve migraine headaches. In discussing the native use of Cannabis and opium products by village doctors in India, who provided 80% of the population with their medical care, the author of a report to the United Nations felt a legitimate role for them was still present (Dwarakanath, 1965): These drugs should be allowed to be used by Ayurvedic and Unani [Arabian tradition] physicians until such time as the benefits of modern medicine are extended to rural areas. Banning their use by the large mass of Ayurvedic and Unani physicians for therapeutic purposes may create a vacuum which may not be easily filled for a long time to come. In another, undated book about medicinal plants of India (Dastur, n.d.), the author stated: Charas is the resinous exudation that collects on the leaves and flowering tops of plants it is the active principle of hemp; it is a valuable narcotic, especially in cases where opium cannot be administered; it is of great value in malarial and periodical headaches, migraine - In recent decades, marijuana has moved to center stage of Western consciousness, not as a medicinal agent, but rather as a perceived drug of abuse and gateway to more harmful addictive substances. Research resumed only slowly, with occasional anecdotal reports by patients of Cannabis' benefits on their illnesses. B.2 More Recent Research and Political Developments on Cannabis: The respected journal Science published an article entitled "Clinical
and Psychological Effects of Marihuana in Man" in 1968. It examined
a variety of clinical responses of nine volunteers smoking Cannabis
under clinical conditions. Some marijuana-naive subjects noted little
subjective change, but manifested some degree of impairment on simple
cognitive tests. Some regular users of the drug actually improved their
performance over that in the sober state. Moderate heart rate increases
were noted, as was conjunctival redness. Peak drug effects were noted
within thirty minutes, and were gone in three hours (Weil, Zinberg &
Nelsen, 1968). A 24-year old single candidate for a master's degree in creative writing claimed to have used marijuana for migraine headaches for a year and a half. At the unofficial suggestion of a neurologist, he experimented with the drug and, finding it effective, used it in lieu of ergotamine tartrate on six or more occasions. Each time he claims to have prevented or substantially attenuated a headache. Those that developed lasted less than 4 hr and were mild in intensity. He had been particularly aware of the relaxing effect of the drug because migraine attacks generally aroused considerable anxiety within him. The effects of smoking for migraine were different from those experienced with a comparable dose on social occasions. Euphoria was absent and drowsiness developed, which helped him to sleep and thus avoid further symptoms. He rated Cafergot PB (with phenobarbital) as slightly superior to marijuana in preventing headaches [This preparation has been particularly prone to provoke "analgesic rebound" with promotion of headache recurrence]. During the past year he claimed to have diminished the frequency of migraine attacks by smoking. The authors said of "Case 3": A 30-year-old married housewife claimed to have used marijuana for the relief of headaches and other minor discomforts for over a year. She discovered its value while smoking and, coincidently, suffering from a headache. She described immediate and lasting relief from a dose similar to that used on social occasions. This was associated with a reduction in tension. In her experience, marijuana had been superior to aspirin, the only other medication she had used. Of "Case 5" they stated: A 25-year-old single graduate student discovered, on the recommendation of a friend, that marijuana relieved headaches. She reported smoking the drug occasionally for that purpose for more than 2 years. Though often complete, the relief she obtained was not consistent. She believed that she had benefited from smoking only about 70% of the time [comparable to the best standard pharmaceuticals in 1997]. Subsequent experimental studies explored these reported analgesic effects
of Cannabis. One article examined pain tolerance thresholds (Milstein
et al., 1975). Both native (8% increase) and experienced subjects (16%
increase) noted statistically significant increases in pain threshold
after smoking Cannabis. The authors also noted no correlation between plasma THC levels and
observed driving impairment. The efficiency of the delivery of a dose by smoking has been estimated to be about 18%, but frequent smokers obtain 23% while infrequent users obtain only 10% (Lindgren et al., 1980). THC and marijuana extracts are also active by mouth; the systemic bioavailability of oral administration is only about 6%, one-third that from smoking (Ohlsson et al., 1980). -Oral doses delay the onset of symptoms for 30 min to over 2 h, as well as prolonging the span of action of the drug. In reviewing a study involving smoking of massive doses daily for a
prolonged period, findings included lower intraocular pressure, serum
testosterone levels, and airway narrowing, but no chromosomal aberrations,
or impairment of immune responses were noted (Cohen, 1976). The myth dies hard that marijuana makes otherwise docile subjects violent. Virtually every experimental study of cannabis that has tried to measure violent or aggressive behavior or thoughts during cannabis intoxication has come to the same conclusion; they are decreased rather than increased. Of addiction, he wrote: In man, a somewhat similar, though mild, withdrawal reaction was uncovered after abrupt cessation of doses of 30 mg of THC given every 4 h p.o. for 10 to 20 days. Subjects became irritable, had sleep disturbances, and had decreased appetite. Nausea, vomiting and occasionally diarrhea were encountered. Sweating, salivation and tremors were autonomic signs of abstinence (Fink et al., 1976). Relatively few reports of spontaneous withdrawal reactions from suddenly stopping cannabis use have appeared despite the extraordinary amount of drug consumed. Five young persons experienced restlessness, abdominal cramps, nausea, sweating, increased pulse rate, and muscle aches when their supplies of cannabis were cut off. Symptoms persisted for 1 to 3 days (Benusan, 1971). The rarity of reports of these reactions may reflect the fact that they are mild- Hollister (1986) ultimately addressed possible medical indications, but his experience with migraine was not broad: Migraine: This indication has not been studied systematically in recent years, although it has a long history. In one patient I treated, the mental effects sought socially caused the patient to abandon treatment. The following year, another article dealt with the issue more directly
(El-Mallakh, 1987). Entitled "Marijuana and Migraine," three
cases were discussed in which abrupt cessation of frequent, prolonged,
daily marijuana smoking were followed by recurrent migraine attacks.
One patient noted subsequent remission of headaches with a return to
episodic marijuana use, while the two others employed "conventional
drugs" successfully. THC's peripheral vasoconstrictive actions
in rats, or its action to minimize serotonin release from the platelets
of human migraineurs (Volfe, Dvilansky & Nathan, 1985), were felt
to be possible explanations of its therapeutic effects. By any measure of rational analysis marijuana can be safely used within a supervised routine of medical care. -There have been occasional instances of panic reaction in patients
who have smoked marijuana. These have occurred in marijuana-naive persons,
usually older persons, who are extremely anxious over the forthcoming
chemotherapy and troubled over the illegality of their having obtained
the marijuana. Such persons have responded to simple person-to-person
communication with a doctor and have sustained no long term mental or
physical damage. Cannabis has also been reviewed in the French literature (Spadone, 1991). Among other points, the author indicated: As to serotonin, the synthesis of 5-HT is stimulated by THC (possibly by intermediary augmentation of corticosteroids) as well as brain 5-HT content. Synaptosomal uptake seems inhibited, while release is favored. [translation EBR] In 1992, subjective preferences of experimental subjects smoking Cannabis,
or ingesting oral THC were assessed (Chait & Zacny, 1992): Oral THC was chosen [over oral placebo] on both trials by 10 of the 11 subjects (P<0.02). These results serious call into question the plausibility of true blinding
with placebo preparations in prospective therapeutic drug studies, especially
those with smoked marijuana. The Journal of the American Medical Association published a recent impassioned commentary (Grinspoon, 1995): Marihuana is also far less addictive and far less subject to abuse than many drugs now used as muscle relaxants, hypnotics, and analgesics. The chief legitimate concern is the effect of smoking on the lungs. Cannabis smoke carries even more tars and other particulate matter than tobacco smoke. But the amount smoked is much less, especially in medical use The main active substance in cannabis, [delta-9]-tetrahydrocannabinol ([delta-9]-THC) has been available for limited purposes as a Schedule II synthetic drug since 1985. This medicine, dronabinol (Marinol), taken orally in capsule form, is sometimes said to obviate the need for medical marihuana. Patients and physicians who have tried both disagree. The dosage and duration of action of marihuana are easier to control, and other cannabinoids in the marihuana plant may modify the action of [delta-9]-THC. The development of cannabinoids in pure form should certainly be encouraged, but the time and resources required are great and at present unavailable. In these circumstances, further isolation, testing, and development of individual cannabinoids should not be considered a substitute for meeting the immediate needs of suffering people. The American Journal of Public Health issued a particularly strong plea (AJPH, 1996), quoted in excerpts: 9513: Access to Therapeutic Marijuana/Cannabis Understanding that while synthetic tetrahydrocannibinol (THC) is available
in pill form, it is only one of approximately 60 cannabinoids which
may have medicinal value individually or in some combination; and In summary, this study showed little, if any, effect of marijuana use on non-AIDS mortality in men and on total mortality in women. Marijuana myths have recently been exhaustively reviewed in book form
(Zimmer and Morgan, 1997). The evidence does not support the reclassification of crude marijuana as a prescribable medicine. However, their study confined itself to the clinical issues of nausea,
appetite stimulation, glaucoma, and spasticity. Methodologically, it
is open to criticism in that the authors screened only the 1975-1996
medical literature, an era during which clinical research on therapeutic
benefits of Cannabis was next to impossible. The authors did not examine
migraine as an issue, failed to review the extensive literature of the
past, and ignored editorial comments and anecdotal accounts by patients.
Cannabis, taken orally or inhaled, has a long history of reportedly
safe and effective use in the treatment and prophylaxis of migraine.
C. Preliminary Studies/Progress Report The principal investigator, Ethan Russo, M.D., has practiced clinical
neurology for fifteen years. He has had a long interest in the study
and treatment of migraine, and is the Medical Director of the St. Patrick
Hospital Inpatient Pain Treatment Program. D. Research Design and Methods D.1 Procedure and Subject Activities: After smoking, the number of inhalations taken and remaining butt length
and weight of the marijuana cigarette will be measured and recorded.
Dr. Russo or the study nurses will supervise administration of all medications.
The statistical design of the study is crossover design. The strength
of the crossover design is that subjectspecific variation may be estimated
and accounted for, and the design permits manifestation of cumulative
drug effects. Under the crossover design, each subject is placed on
a single protocol for a fixed time period (a session), during which
a number of visits for migraine treatment occur, and then the subject
is switched to the alternate protocol. The proposed design specifies
that 20 subjects will be randomly allocated to each protocol and that
7 visits per protocol are expected, based on the average frequency of
migraine attacks for patients in the study population. Visits per 3-month
protocol are limited to 10. D.3 Location of Research: The administration of these medications will take place in the Neurosciences Department at the Western Montana Clinic in space rented from St. Patrick Hospital. The Joint IRB has accepted this plan (Appendix). Precautions described below will be employed to manage risks to patients, and reduce ambient smoke exposure. Hours of availability are discussed above, Section D.1. D.4 Benefits: Results of this project may be valuable for migraineurs and the professionals
who treat them because there is a strong need for additional medications
that will effectively this condition in its acute state. At this time,
the best available medication, injected sumatriptan (Imitrex) has been
ineffective in up to 30% of patients, or has produced undesirable side
effects for up to 66% when administered subcutaneously (Mathew, 1997).
Sumatriptan is the current "gold standard". Sumatriptan non-responders
have been studied (Visser et al., 1996). Such patients may be obese,
or take the medicine too early. Beyond that, the study found no features
distinguishing responders from non-responders. The PI would add another
observation from clinical experience: people with the chronic daily
headache subset of migraine respond poorly to subcutaneous sumatriptan.
Because this proposal focuses on migraineurs with episodic attacks,
CDH patients will be excluded. D.5 Gender and Minority Inclusion: This study will be open to all adults subject to the medical exclusions noted above. We encourage participation of women who are not pregnant or lactating, especially considering that women suffer a higher incidence of migraine in most studies. Efforts will be made to ensure reasonable birth control methods in participating women in child-bearing years. The local population of Missoula, MT contains small minorities of Native Americans and Hmong refugees. All will be welcome to participate. E.1 Population Characteristics: E.2 Research Material and Data: E.3A Recruitment: please see D.1 above. E.3B Informed Consent: E.4 Potential Risks: Acute Effects For these reasons, pregnant or lactating women, those with past or
family history of psychosis, patients with coronary or hypertensive
risk factors, patients taking MAO-inhibitors or having previous problems
with substance or analgesic abuse, etc., will be excluded form participation
in the study. Patients with the chronic daily headache variant of migraine
will also be excluded, as will those with history sumatriptan allergy
or significant chest pain. Patients will also undergo a detailed history
and physical examination by Dr. Russo to screen for additional exclusions.
As above, efforts will be made to ensure reasonable birth control methods
in study subjects of child-bearing potential. E.5 Privacy Issues: E.6 Risks vs. Benefits: Sponsorship: G. Literature Cited: Agurell, S., Halldin, M., Lindgren, J-E, Ohlsson, A., Widman, M., Gillespie, H. and Hollister, L., "Pharmacokinetics and Metabolism of Delta-1- Tetrahydrocannabinol and Other Cannabinoids with Emphasis on Man," Pharmacol. Rev. 38: 21-43, 1986. AJPH, "Access to Therapeutic Marijuana/Cannabis," Amer. J. Public Health 86:441-442, 1996. Artamonov, M.I., "Frozen Tombs of the Scythians," Scientific American 212(5):101-109, 1965. Auster, F., and Schafer, J., Arzneipflanzen (7. Lieferung), Veb Georg Thieme, Leipzig, 1955. Barinaga, M., "Pot, Heroin Unlock New Areas for Neuroscience," Science 258:1882-1884, 1992. Beckman, H., Treatment in General Practice, Saunders, Philadelphia, 1938. Benet, S., "Early Diffusion and Folk Uses of Hemp." In: V. Rubin (Ed.), Cannabis and Culture, Mouton, The Hague, 1975. 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INTERVIEW PROTOCOL
1. Have you been formally diagnosed with migraines? Yes No How often do you get headaches? 2. Where is the pain located?
3. Is it worse on one side than the other? Yes No 4. Do other family members have headaches? Yes No 5. If so, what relationship are they?
6. Did you feel the need to lie on the couch with a cool damp cloth on your head to relieve headache? Yes &nbs p; No 7. Is there a beating quality to the pain? Yes No 8. If you climb stairs, exert yourself, or bend over when you have a headache, is there a beating quality? Yes No 9. When you have a headache do you feel sick to your stomach, lose your appetite, or vomit? Yes No 10. Or, when you have a headache, are you able to sit up to a full meal? Yes No 11. When you have a headache do you experience any visual problems? Yes No 12. If so, is there blurring, or do you see spots or sparkles? (circle which ones) 13. Are your eyes sensitive to light? Yes No 14. Do you prefer to be in a dark room? Yes No 15. Can you tolerate bright sunlight during a headache? Yes No 16. Does loud music bother you then? Yes No 17. Do certain sounds bother you? Yes No 18. Are you currently under a doctor's care? Yes No 19. Have you had cardiac problems in the past or currently? Yes No 20. Are you currently pregnant or breast- feeding? Yes No 21. Have you ever been diagnosed with a psychiatric diagnosis? Yes No If so, list diagnosis
22. Has anyone in your family been diagnosed with a psychiatric disorder? Yes No If so, list diagnosis 23. Are you currently taking any of the following types of medication: antidepressants, anticonvulsants (i.e., seizure medication), or tranquilizers? Yes No 24. Have you used hallucinogens or opiates [e.g., LSD, Mescaline, Peyote, STP, DMT, Psilocybin (mushrooms), Heroin, Morphine, Opium]? Yes No 25. Have you used marijuana recreationally? Yes No 26. Have you used crack, cocaine, or Ecstasy? Yes No 27. Have you used inhalants? Yes No 28. Have you used stimulants? Yes No 29. Have you used anti-anxiety agents or sleeping medications? Yes No 30. Have you used pain medication? Yes No 31. Have you been treated for alcoholism? Yes No 32. Are you taking any medications not already listed? Yes No 33. This treatment involves the use of Dronabinol (synthetic THC), meperidine (Demerol) and Cannabis (marijuana). Are you willing to use this medication as part of this research, recognizing its government approval and legality for this study? Yes No 34. This treatment requires that you be accompanied to and from treatment by a licensed driver who will be able to escort you home. Is someone available and willing to do this for you? Yes No 35. Is your job subject to drug testing? Yes No 36. Have you received sumatriptan injections for your migraines? Yes No 37. How many times?
38. Was it effective for the pain? Yes No 39. Was it effective for the nausea? Yes No 40. Was it effective for photophobia? Yes No 41. Did sumatriptan give you side effects? Yes No 42. If so, what were they?
43. Would you want to have sumatriptan injections again for your headaches? Yes No 44. Why, or why not?
Subject # Functioning Questionnaire: 1 Hour Post Treatment Please complete the following questions as carefully as you can, and return to the study nurse. 1. Do you have a job? Yes No A. If yes, could you work with the way you felt immediately following treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbp; &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% B. If yes, could you work with the way you feel right now? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate) 0% 1 0% 20% &nb sp; 30% 40% 50% 60% 70% &n bsp; 80% 90% ; 100% 2. Are you a student? Yes No A. If yes, could you study with the way you felt immediately following treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% 1 0% 20% &nb sp; 30% 40% 50% 60% 70% &n bsp; 80% 90% ; 100% B. If yes, could you study with the way you feel right now? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% 1 0% 20% &nb sp; 30% 40% 50% 60% 70% &n bsp; 80% 90% ; 100% C. If yes, could you have gotten anything out of class with the way you felt right after the treatment? Yes&nbs p; No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% 1 0% 20% &nb sp; 30% 40% 50% 60% 70% &n bsp; 80% 90% ; 100% D. If yes, could you have gotten anything out of class with the way you feel right now? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% 1 0% 20% &nb sp; 30% 40% 50% 60% 70% &n bsp; 80% 90% ; 100% 3. How would you rate your pain right now? (Please put a slash at the number that describes your current level of pain where 0 is no pain and 10 is intense pain). 0 &n bsp; 1 2 &nbs p; 3 4 5 6& nbsp; 7 &nbs p; 8 9 10 No pain &nb sp; Neutral & nbsp; ; &nb sp; Intense pain 4. How would you rate your nausea right now? (Please put a slash at the number that describes your current level of nausea where 0 is no nausea and 10 is severe nausea). 0 &n bsp; 1 2 &nbs p; 3 4 5 6& nbsp; 7 &nbs p; 8 9 10 No nausea &nbs p; &n bsp; Neutral &nb sp; & nbsp;Severe nausea 5. How would you rate your sensitivity to light? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 &n bsp; 1 2 &nbs p; 3 4 5 6& nbsp; 7 &nbs p; 8 9 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 6. How would you rate your sensitivity to sound? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 7 & nbsp; 8 9 &nb sp; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 7. Please describe any negative experiences you had during or after the treatment.
8. What medicine would you say that you received?
Subject # Functioning Questionnaire- 2 hours Post Treatment Please complete the following questions as carefully as you can, and return them to the study nurse. 1. What time is it right now? 2. Do you have a job? Yes No If yes, could you work with the way you felt 2 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 3. Are you a student? Yes No If yes, could you study with the way you feel 2 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% B. If yes, could you have gotten anything out of class with the way you feel 2 hours after treatment? Yes &nbs p; No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 4. How would you rate your pain 2 hours after treatment? (Please put a slash at the number that describes your level of pain where 0 is no pain and 10 is severe pain). 0 1& nbsp; 2 &nbs p; 3 4 5 6 & nbsp; 7 8&nb sp; 9 10 No pain &nb sp; Neutral & nbsp; ; &nb sp; Severe pain 5. How would you rate your nausea 2 hours after treatment? (Please put a slash at the number that describes your current level of nausea where 0 is no nausea and 10 is severe nausea). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 No nausea &nbs p; &n bsp; Neutral &nb sp; Severe nausea 6. How would you rate your sensitivity to light 2 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 7. How would you rate your sensitivity to sound 2 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 8. Please describe any negative experiences you had since the treatment.
9. What medicine would you say that you received?
Subject # Functioning Questionnaire- 3 hours Post Treatment Please complete the following questions as carefully as you can 3 hours after treatment, and return it to the study nurse. 1. What time is it right now? 2. Do you have a job? Yes No If yes, could you work with the way you feel 3 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 3. Are you a student? Yes No A. If yes, could you study with the way you feel 3 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% B. If yes, could you have gotten anything out of class with the way you feel 3 hours after treatment? Yes &nbs p; No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 4. How would you rate your pain 3 hours after treatment? (Please put a slash at the number that describes your level of pain where 0 is no pain and 10 is severe pain). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 No pain &nb sp; Neutral & nbsp; ; &nb sp; Severe pain 5. How would you rate your nausea 3 hours after treatment? (Please put a slash at the number that describes your current level of nausea where 0 is no nausea and 10 is severe nausea). 0 1& nbsp; 2 &nbs p; 3 4 5 6 & nbsp; 7 8&nb sp; 9 10 No nausea &nbs p; &n bsp; Neutral &nb sp; Severe nausea 6. How would you rate your sensitivity to light 3 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 7. How would you rate your sensitivity to sound 3 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 8. Please describe any negative experiences you have had since the treatment.
9. What medicine would you say that you received?
10. Do you need the rescue medication?
Subject # Functioning Questionnaire- 4 hours Post Treatment Please complete the following questions as carefully as you can 4 hours after treatment, and return it to the study nurse. 1. What time is it right now? 2. Do you have a job? Yes No If yes, could you work with the way you feel 4 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 3. Are you a student? Yes No A. If yes, could you study with the way you feel 4 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% B. If yes, could you have gotten anything out of class with the way you feel 4 hours after treatment? Yes &nbs p; No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% 1 0% 20% &nb sp; 30% 40% 50% 60% 70% &n bsp; 80% 90% ; 100% 4. How would you rate your pain 4 hours after treatment? (Please put a slash at the number that describes your level of pain where 0 is no pain and 10 is severe pain). 0 1& nbsp; 2 &nbs p; 3 4 5 6 & nbsp; 7 8&nb sp; 9 10 No pain &nb sp; Neutral & nbsp; ; &nb sp; Severe pain 5. How would you rate your nausea 4 hours after treatment? (Please put a slash at the number that describes your current level of nausea where 0 is no nausea and 10 is severe nausea). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 No nausea &nbs p; &n bsp; Neutral &nb sp; Severe nausea 6. How would you rate your sensitivity to light 4 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 7. How would you rate your sensitivity to sound 4 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 8. Please describe any negative experiences you have had since the treatment.
9. What medicine would you say that you received?
10.Did you receive the rescue medication? YES______ &n bsp;NO_____ 11. If so, what effects has it had?
Subject # Functioning Questionnaire- 24 hours Post Treatment Please complete the following questions as carefully as you can 24 hours after treatment. Then return them in the self-addressed, stamped envelope provided. 1. What time is it right now? 2. Do you have a job? Yes No If yes, can you work with the way you feel 24 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 3. Are you a student? Yes No A. If yes, can you study with the way you feel 24 hours after treatment? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% 0% & nbsp; 20% 30% &nbs p; 40% 50%& nbsp; 60% & nbsp; 70% 80% &nbs p; 90% 100% B. If yes, can you have get anything out of class with the way you feel 24 hours after treatment? Yes &nbs p; No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 4. How would you rate your pain 24 hours after treatment? (Please put a slash at the number that describes your level of pain where 0 is no pain and 10 is severe pain). 0 1& nbsp; 2 &nbs p; 3 4 5 6 & nbsp; 7 8&nb sp; 9 10 No pain &nb sp; Neutral & nbsp; ; &nb sp; Severe pain 5. How would you rate your nausea 24 hours after treatment? (Please put a slash at the number that describes your current level of nausea where 0 is no nausea and 10 is severe nausea). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 No nausea &nbs p; &n bsp; Neutral &nb sp; Severe nausea 6. How would you rate your sensitivity to light 24 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 7. How would you rate your sensitivity to sound 24 hours after treatment? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 8. Please describe any negative experiences you have had since the treatment.
9. What medicine would you say that you received in the session?
Subject # Pre-Treatment Questionnaire 1. How many headaches have you had since the last treatment? 2. How satisfied were you with the last treatment? (Circle the appropriate number). 1 2 3 & nbsp; 4 5 &nb sp; 6 7 ; 8 9& nbsp; 10 Not satisfied &n bsp; Neutral &nb sp; Extremely Satisfied 3. Please write any comments that you would like to share (i.e., problems, concerns, and likes/dislikes).
4. Has your medication use changed at all (type, frequency of use) since your last study treatment?
5. Please write any comments that you would like to share (i.e., problems, concerns, and likes/dislikes).
6. What time is it right now? 7. Do you have a job? Yes No If yes, can you work with the way you feel right now? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 8. Are you a student? Yes No A. If yes, can you study with the way you feel right now? Yes No How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% If yes, could you get anything out of class with the way you feel right now? Yes No C. How effective would you be? (Please put a slash at the percentage of effectiveness you would anticipate). 0% &nbs p;10% 20% & nbsp; 30% 40% &nbs p; 50% &nbs p;60% 70% & nbsp; 80% 90% &nbs p; 100% 9. How would you rate your pain right now? (Please put a slash at the number that describes your level of pain where 0 is no pain and 10 is severe pain). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 No pain &nb sp; Neutral & nbsp; ; &nb sp; Severe pain 10. How would you rate your nausea right now? (Please put a slash at the number that describes your current level of nausea where 0 is no nausea and 10 is severe nausea). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 No nausea &nbs p; &n bsp; Neutral &nb sp; Severe nausea 11. How would you rate your sensitivity to light right now? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive 12. How would you rate your sensitivity to sound right now? (Please put a slash at the number that describes your current level of sensitivity where 0 is none and 10 is extremely sensitive). 0 1 2 & nbsp; 3 4 &nb sp; 5 6 ; 7 8& nbsp; 9 &nbs p; 10 Not sensitive &n bsp; Neutral &nb sp; & nbsp; Extremely sensitive
Statement of Informed Consent
Pilot Study: Inhalation of Pyrolysed Cannabis sativa vs. Oral Dronabinol, and Injected Sumatriptan as Treatment for Acute Migraine: A Prospective Double-blind Crossover Study Principal Investigator: Ethan Russo, M.D.
The purpose of this study is to enhance knowledge of, and to examine and compare the efficacy of, three different drug treatments and two placebo treatments for migraines. These include: Dronabinol (Marinol, synthetic THC, the active ingredient of marijuana). This project is important because there is a need for new medications
that will effectively treat acute migraines. Some patients and their
doctors have claimed that smoked Cannabis (marijuana) is helpful in
treating migraines, and we would like to test that idea experimentally.
Alternative medications and non-drug treatments for migraine exist in
addition to the study medicines. Questions about alternative treatments
should be directed to your regular physician or care provider. As one of about 40 participants in this study, you will be administered
each of these treatments by Dr. Ethan Russo, a neurologist, or research
nurses during the study period of two three month blocks with a two
week break in between. Each subject will be treated with injected sumatriptan,
or will receive a capsule and smoke a special cigarette. Both subjects
and administrators will be "blinded." That is a way of saying
that neither side will know whether it is true marijuana or dronabinol
that is received as opposed to placebo. No one will receive both true
marijuana and true dronabinol in a single session, and no one will receive
only two placebos in a session. Two blood samples will be taken during
each session, with the exception of the sumatriptan sessions. You will
also be asked to respond to oral and written questions concerning your
impressions of the treatments during four hours. If you are still feeling
badly after three hours, you will have the option of receiving "rescue
medication," in the form of an injection of magnesium sulfate.
After four hours, you may return home with your "designated driver,"
or via taxi. There are several potential benefits of this research. The data we collect will provide information about the effects of these drug treatments on migraines and about patients' ability to function following each treatment. This data may or may not help to make migraine treatment more effective for you and other patients in the future. Potential risks of the study may include decreased ability to function
after a drug treatment, physical discomfort from injections of sumatriptan
or blood drawing. Some people become anxious after exposure to THC from
dronabinol or Cannabis, especially if they have not previously experienced
it. However, this side effect is usually brief, and we will make efforts
to have you as comfortable as possible during the testing procedures.
In the unlikely event of unforeseen complications or injury, appropriate medical intervention will be arranged for you, and billed through your insurance carrier, if possible. The researchers will not be able to provide any other compensation to you if you are injured. Monetary reimbursement of $30 will be provided for your effort for
each of the treatment sessions that take place during data collection.
There will be no cost to you for the medications or the visits with
Dr. Russo. You may be withdrawn from this study without your consent by the investigators for just cause, and this will not be subject to appeal. We hope that this will not become necessary. Because of the sensitive political nature of this investigation, it is our preference that suitable discretion be employed by participants, and not discussed with other than appropriate individuals prior to its completion. If the participants have questions or concerns about any aspect of this project, please feel free to contact the researchers, Jeannine B. Mielke and Laura Taylor Painter; the faculty supervisor, Stuart Hall, Ph.D., or the principal investigator, Ethan Russo, M.D.: Laura T. Painter/Jeannine B. Mielke Ethan Russo, M.D.
Jim Gouaux, M.D./ Ms. Lola Goss
Signature:_______________Date:__________
Please include your name and address if you wish to receive a summary of the research findings when this study is complete. The expected completion date is July 2000. Name:________________ Address:_____________
SAMPLE ADVERTISEMENT The following is a sample of the advertisement we are likely to employ: MIGRAINE RESEARCH: CALL FOR PATIENTS "We are looking for individuals to participate in a NIH-approved research project examining the effectiveness of experimental medications in the treatment of migraine. Participants must be over 18, and have three or more severe headaches per month. Treatment with this experimental protocol will be provided free of charge for six months. Monetary reimbursement will be available. Contact the researchers at (telephone number)." |