NOTE: This is an archive site - we now have a new site.
Cannabis for Migraine Treatment:
Background:
MAPS just donated $1,000 to Dr. Ethan Russo, U. of Montana, for the
preparation of a grant application to the National Institutes of Health
for a study investigating the use of smoked marijuana and oral THC in
the treatment of migraine headaches. Dr. Russo is currently the only
researcher in the United States of whom we are aware trying to obtain an
NIH grant to study the medical use of marijuana in a patient population .
Dr. Russo's previous NIH grant application was rejected and he is
submitting a revised application for the July 1 deadline. This latest
$1000 grant is for a statistician to do sample size calculations for the
revised protocol. MAPS has previously awarded Dr. Russo two grants for
the preparation of the NIH applications: $1,500 in March 1998 and $3,500
in 1997.
Dr. Donald Abrams, UC San Francisco, is the only researcher in the
United States approved to study the use of smoked marijuana in a patient
population. Dr. Abrams was also assisted by MAPS (with two $5,000
grants) in the preparation of his NIH grant applications. Dr. Abrams
expects to receive his supplies of marijuana from NIDA very soon and
will then begin his 18 month study, for which he received a $978,000
National Institutes of Health grant.
More information about the efforts of Dr. Abrams and Dr. Russo can be found in the back issues of the MAPS Bulletin www.maps.org/news-letters/ and the MAPS Medical Marijuana Research page www.maps.org/mmj/.
The Once and Future Historical and Scientific Review
Ethan Russo, M.D.
Clinical Child and Adult Neurologist
Clinical Assistant Professor of Medicine, University of Washington
Adjunct Associate Professor of Pharmacy, University of Montana
Department of Neurology
Western Montana Clinic
Abstract:
Cannabis, or marijuana, has been used for centuries for both
symptomatic and prophylactic treatment of migraine. It was highly esteemed
as a headache remedy by the most prominent physicians of the age between
1874 and 1942, remaining part of the Western pharmacopoeia for this
indication even into the mid-twentieth century. Current ethnobotanical
and anecdotal references continue to refer to its efficacy for this malady,
while biochemical studies of THC and anandamide have provided a scientific
basis for such treatment.
The author believes that controlled clinical trials of Cannabis in acute
migraine treatment are warranted.
Introduction:
One of the basic tenets of medical history is that remedies fall in and out
of favor. Once supplanted, most pharmaceuticals fail to re-attain a
position of prominence. Very few are popular for many decades.
Not many physicians today are aware of the prominence that Cannabis
drugs once held in medical practice. Problems with quality control and an
association with perceived dangerous effects sounded the death knell for
Cannabis as a recognized Western therapy. Other medicines that are far more
potentially damaging than Cannabis remain in our pharmocopeias because of
recognized medical indications: opiates for pain control, amphetamines for
narcolepsy and attention deficit hyperactivity disorder, etc. Thalidomide,
which was banned due to its role in birth defects, may be effecting a
therapeutic revival. Even the lowly leech is once again the object of
serious medical investigation.
This study will examine the history of Cannabis use for one indication,
that of headache treatment, its scientific rationale, and possible future
as an alternative therapeutic agent.
Historical and Ethnobotanical Usage of Cannabis in Migraine Treatment:
Headaches have likely afflicted man throughout history. Archeological
records substantiate an ancient association between man and the plant genus
Cannabis, plant family, Cannabaceae. Its botanical origin has been debated
to be as far east as China, but most experts suspect it to be in Central
Asia, possibly in the Pamir Plains (Camp, 1936). Some botanists have
maintained Cannabis as monotypic genus, while others (Schultes et al.,
1974) have provided convincing documentation of three Cannabis species:
sativa, indica, and ruderalis. All contain the psychoactive chemical
delta-9-tetrahydrocannabinol (THC) in varying degree.
Use of Cannabis fibers to make hemp has been documented as early as
4000 BC by Carbon-14 dating (Li, 1974), and that use has been maintained
continuously up to the present day. Its seed grain was an ancient human
foodstuff, which may have lead to an early recognition of its medicinal
use. The first records of the latter seem to be in the P=EAn-tsao Ching, a
traditional herbal written down in the first two centuries AD, but said to
be based on the oral traditions passed down from the Emperor Sh=EAn-nung in
the third millenium BC. The text noted that the plant fruits "if taken in
excess will produce hallucinations (literally "seeing devils") (Li, 1974).
The Zend-Avesta, the holy book of Zoroastrianism, which survives only in
fragments, dating from around 600 BC in Persia, alludes to the use of Banga
in a medical context, and it is identified as hemp by the translator (Darmesteter, 1895).
The classical Greek literature also documents knowledge of the inebriating
actions of Cannabis. Herodotus, circa 450 BC, described how the Scythians
set up tents, heated stones and threw Cannabis seeds or flowering tops upon
them to create a vapor, and "the Scythians, delighted, shout for joy." The
Greek physicians Dioscorides and Galen expounded on medical indications,
mainly gastrointestinal (Brunner, 1977).
The Atharva Veda of India, dated to between 1400 and 2000 BC referred to a
sacred grass, bhang, and medicinal references to Cannabis were cited by
Susrata in the sixth to seventh centuries AD (Chopra and Chopra, 1957) and
included indication for its use for headache (Dwarakanath, 1965).
O'Shaughnessy introduced the medical use of Cannabis indica, or "Indian
hemp," to the West in 1839 (Walton, 1938; Mikuriya, 1969). His treatise on
the subject supported the utility of an extract in patients suffering from
rabies, cholera, tetanus, and infantile convulsions.
Throughout the latter half of the nineteenth century, many prominent
physicians in Europe and North America advocated the use of extracts of
Cannabis indica for the symptomatic and preventive treatment of headache.
Proponents included Weir Mitchell in 1874, E.J. Waring in 1874, Hobart Hare
in 1887, Sir William Gowers in 1888, J.R. Reynolds in 1890, J.B. Mattison
in 1891, et al., (Walton, 1938; Mikuriya, 1969). Cannabis was included in
the mainstream pharmacopeias in Britain and America for this indication.
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." This statement supports its use for both acute and prophylactic
treatment of migraine.
In 1916, in a quotation attributed to Dr. Dixon, Professor of Pharmacology,
Kings' College, and the University of Cambridge (Ratnam, 1916), reference
is specifically made to the therapeutic effects of smoked Cannabis for
headache treatment. He stated, "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."
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."
Nevertheless, it retained adherents for a variety of medical indications,
throughout the early decades of the twentieth century. In 1938 Robert
Walton published a comprehensive review of Cannabis, with botanical,
historical, chemical and political discussions (Walton, 1938). After
discussing the abuse issue, he stated his belief that the political action
that had rendered marijuana illegal in the U.S.A. in 1937 (and which the
American Medical Association vigorously opposed), should not serve to
prohibit further medical use and scientific investigation of Cannabis'
possible applications. Walton referred to twelve major authorities on its
efficacy for migraine, and only one detractor.
In 1941, Cannabis preparations were dropped from the United States
Pharmacopeia (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).
This practitioner seemed to prefer Cannabis to ergotamine tartrate, which
remains in the migraine armamentarium, some fifty-five years later.
Thus, Cannabis was touted in eight consecutive decades in the mainstream
Western medical literature as a, or the, primary treatment for migraine.
As late as 1957, despite governmental controls in that country, Cannabis
drugs retained a role in the indigenous medicine of India (Chopra and
Chopra, 1957), and other countries.
In the 1960's marijuana moved to center stage of Western consciousness, and
attained a degree of notoriety sufficient to render medical usage
inconceivable to most. Medical research has resumed only recently, spurred
on by anecdotal reports of patients who serendipitously discovered its
benefits on their maladies.
Modern Research Developments on Cannabis:
In 1974, the first of several studies appeared examining issues of pain
relief with Cannabis (Noyes and Baram, 1974). This article examined five
case studies of patients who volitionally experimented with the substance
to treat painful conditions. Three had chronic headaches, and found relief
by smoking Cannabis that was comparable, or superior to ergotamine tartrate
and aspirin.
One subsequent study of Cannabis pertained to pain tolerance in an
experimental protocol (Milstein et al., 1975). A statistically significant
increase in pain threshold was observed after smoking Cannabis in both
naieve (8% increase) and experienced subjects (16% increase).
Another trial involved oral THC in cancer patients (Noyes et al., 1975a).
They observed a trend toward pain relief with escalating doses significant
to the P<0.001 level. The peak effect occurred at three hours with doses of
10 and 15 mg., but not until five hours after ingestion of 20 mg.
Subsequently, the analgesic effect of THC was compared to codeine (Noyes et
al., 1975b). In essence, 10 mg. of oral THC vs. 60 mg. of codeine, and 20
mg. of THC vs. 120 mg. of codeine relieved the subjective pain burden of
patients by similar decrements. The effects of 10 mg. of THC were well
tolerated, but at 20 mg., sedation, and psychic disturbances bothered
manyof the elderly Cannabis-na=EFve subjects.
In the 1980's more comprehensive data on pharmacological effects of
Cannabis and its derivative, THC became available. In 1983, research with
varying potencies of smoked Cannabis demonstrated some correlation between
serum THC levels and subjective "high" (Chiang and Barnett, 1983).
Additionally, experimental subjects were able to distinguish the potency of
the various samples with accuracy.
In a forensic review (Mason et al., 1985), the issue of marijuana's effect
on driving was addressed, and it was indicated that isolated reports of
adverse outcomes secondary to impairment by Cannabis as a sole inebriant
were rare. The authors concluded that there was no suitable correlation
between plasma or blood levels of THC and the degree of apparent impairment
a human might exhibit.
In 1986 the journal Pharmacological Reviews devoted an entire issue to
Cannabis and cannabinoids. In "Cellular Effects of Cannabinoids" (Martin,
1986), the author noted their analgesic properties, but reported that the
mode of action was not blocked by naloxone, and seemed to work
independently of opioid mechanisms.
Another article examined pharmacokinetics (Agurell et al., 1986). Many
facets were presented, including their findings that smoking a standard
marijuana cigarette destroyed 30% of available THC.
The final article of the issue was entitled "Health Aspects of Cannabis"
(Hollister, 1986). Pertinent points made included dose delivery efficiency
of THC by inhalation of 10% in marijuana-na=EFve vs. 23% in experience
smokers. Oral bioavailability for THC was only about 6%, and onset of
effects was not seen for 30-120 minutes.
Smoking of massive Cannabis doses daily for a prolonged period produced
lower intraocular pressure, serum testosterone levels, and airway
narrowing, but no chromosomal aberrations, or impairment of immune
responses were noted (Cohen, 1976).
Other "marijuana myths" were unsupported by careful review of the
literature. While aggravation of pre-existing psychotic conditions by
marijuana use was documented, no cause and effect relationship was noted.
Similarly, chronic use studies in Jamaica (Comitas et al., 1976), revealed
no deficits in worker motivation or production. Two studies of brain
computerized tomography (CT scan) refuted prior claims of heavy use
producing cerebral atrophy (Co et al, 1977; Kuehnle et al., 1977).
With respect to behavior, Hollister refuted the tenet that depicted
Cannabis as a contributor to violent and aggressive behavior. Concerning
addiction, he noted minimal withdrawal symptoms of nausea, vomiting,
diarrhea, and tremors in some experimental subjects after very heavy
chronic usage. Such effects were brief and self-limited.
The next year, an article entitled "Marijuana and Migraine" (El-Mallakh,
1987), presented three cases in which abrupt cessation of frequent,
prolonged, daily marijuana smoking were followed by migraine attacks. One
patient noted subsequent remission of headaches with episodic marijuana
use, while conventional drugs successfully treated the others. The author
hypothesized that THC's peripheral vasoconstrictive actions in rats, or its
action to minimize serotonin release from the platelets of human
migraineurs (Volfe et al., 1985), might explain its actions.
In 1988 action was initiated through the DEA to reclassify marijuana to
Schedule 2, potentially making it available for prescription to patients.
The DEA administrative law judge, Francis Young, reviewed a tremendous
amount of testimony from patients, scientists, and politicians in rendering
his ruling. Although a medical indication of marijuana for migraine was not
considered, its use was approved as an anti-emetic, an anti-spasticity drug
in multiple sclerosis and paraplegia, while its utilization in glaucoma was
considered reasonable. He stated, "By any measure of rational analysis
marijuana can be safely used within a supervised routine of medical care."
In 1992, a study examined subjective preferences of experimental subjects
smoking Cannabis, or ingesting oral THC (Chait and Zacny, 1992). Ten
subjects in two trials preferred smoking active Cannabis over placebo,
while ten of eleven preferred oral THC to placebo. These results call into
serious question the plausibility of true blinding with placebo
preparations in prospective therapeutic drug studies of marijuana,
especially when smoked.
A more profound understanding of Cannabis, THC, and their actions in the
brain has occurred with the discovery of an endogenous cannabinoid in the
human brain, arachidonylethanolamide, named anandamide, from the Sanskrit
word ananda, or "bliss" (Devane et al., 1992). This ligand inhibits cyclic
AMP in its target cells, which are widespread throughout the brain, but
demonstrate a predilection for areas involved with nociception (Herkenham,
1993). The exact physiological role of anandamide is unclear, but
preliminary tests of its behavioral effects reveal actions similar to those
of THC (Fride and Mechoulam, 1993).
Additional research sheds light on possible mechanisms of therapeutic
action of the cannabinoids on migraine. An inhibitory effect of anandamide
and other cannabinoid agonists on rat serotonin type 3 (5-HT3) receptors
was demonstrated (Fan, 1995). This receptor has been implicated as a
mediator of emetic and pain responses. In 1996, a study in rats
demonstrated antinociceptive effects of delta-9-THC and other cannabinoids
in the periaqueductal gray matter (Lichtman et al., 1996). The PAG has been
frequently cited as a likely anatomic area for migraine generation (Goadsby
and Gundlach, 1991).
The understanding that Cannabis and THC effect their actions through
natural cerebral biochemical processes has intensified the public debate on
medical benefits of marijuana. In 1993, a book entitled Marihuana: The
Forbidden Medicine (Grinspoon and Bakalar, 1993) examined a variety of
claims for ailments treated by marijuana, and included an entire section on
migraine. One clinical vignette discussed at length the medical odyssey of
a migraineur through failures with standard pharmaceuticals, and ultimate
preference for small doses of smoked marijuana for symptom control.
The editor of the British Medical Journal (Smith, 1995) recently wrote an
editorial espousing moderation in the drug war. The Journal of the American
Medical Association published a supportive commentary in 1995 (Grinspoon,
1995). The author rated the respiratory risks potent medical marijuana as
low, and pointed out the contradiction of the Schedule 2 status of
synthetic THC, dronabinol, while its natural source, marijuana remained a
Schedule 1 product, and thus unavailable for legal use to patients who
might prefer its easier dose titration. Grinspoon raised as a theoretical
possibility the synergistic effects of the whole plant and its components
as compared to pure THC.
The American Journal of Public Health issued its plea (AJPH, 1996), to
allow access to medical marijuana as an Investigational New Drug (IND).
The Australian government (Hall et al., 1995) recently compiled a recent
exhaustive review of sequelae of Cannabis use. In the summary, it states:
Acute Effects
- anxiety, dysphoria, panic and paranoia, especially in na=EFve users;
- cognitive impairment, especially of attention and memory, for the duration of intoxication;
- psychomotor impairment, and probably an increased risk of accident if an
intoxicated person attempts to drive a motor vehicle, or operate machinery;
- an increased risk of experiencing psychotic symptoms among those who are
vulnerable because of personal or family history of psychosis;
- an increased risk of low birth weight babies if cannabis is used during pregnancy.
Surely, not all in the medical establishment are convinced of the relative
safety or benefit of Cannabis for medical usage. In a recent review (Voth
and Schwartz, 1997) the authors concluded, "The evidence does not support
the reclassification of crude marijuana as a prescribable medicine."
However, their study was far from comprehensive, confining itself to the
clinical issues of nausea, appetite stimulation, glaucoma, and spasticity.
Methodologically, it was flawed in that only the medical literature from
1975-1996 was screened, an era during which it was quite difficult to
initiate research seeking to support medical indications for Cannabis.
These authors did not examine migraine as an indication for Cannabis usage,
nor did they review the extensive literature of the past. The debate on the
subject of "medical marijuana" has extended to the World Wide Web, and
includes myriad postings with anecdotal attestations of efficacy for a
variety of indications.
Various investigators have examined the roles of different smoke delivery
systems (Gieringer, 1996). From these studies, it is clear that
vaporization of marijuana makes it possible to deliver even high doses of
THC to the lungs of a prospective patient far below the flash point of the
Cannabis leaf, eliminating a fair amount of smoke, containing tar and other
possible carcinogens. However, the marijuana joint was about as effective
as any examined smoking device, including waterpipes, in providing a
favorable ratio of THC to tar and other by-products of smoking. A
standardized smoking procedure for use of Cannabis in medical research has
been developed (Foltin et al., 1988).
Suppository preparations of Cannabis have been used to advantage in the
past, and may be an acceptable form of administration for the migraineur,
although dose titration would be less available.
Discussion:
Despite the development of serotonin 1D-agonist medications, migraine
remains a serious public health issue. An estimated 23 million Americans
suffer severe migraine. Of these, 25% have four or more episodes per month,
and 35% have one to three severe headaches each month (Stewart et al.,
1992). In economic terms, the impact of migraine is enormous: an
estimated14% of females, and 8% of males missed a portion of, or an entire day of
work or school in one month (Linet et al., 1989). Migraine has been
estimated to account for an economic impact of $1.2 to $17.2 billion
annually in the U.S.A. in terms of lost productivity (Lipton et al., 1993).
In 1990 studies were published outlining the biochemical basis of migraine
treatment in serotonin receptor pharmacology (Peroutka, 1990). It was this
research that led to the development of the first drugs active on serotonin
receptor subtypes, sumatriptan, and ondansetron.
However, despite the justifiable success of sumatriptan in treating acute
migraine, problems remain. Although rapidly active subcutaneously, its oral
absorption is relatively slow, and often unreliable in the migraineur.
Sumatriptan and its analogues are ineffective when administered in the
"aura phase" of classic migraine (Ferrari and Saxena, 1995). Additionally,
headache recurrence after "triptan" 5-HT1D agonist agents is a not
infrequent occurrence. Unfortunately, repetitive dosing, and development of
agents with longer half-lives does not seem to avert the issue (Ferrari and
Saxena, 1995).
Another curiosity in the development of sumatriptan is its relative
inability to pass the blood-brain barrier. Once more, the development of
newer agents with improved central nervous system penetration has not
necessarily improved efficacy, but does increase the likelihood of side
effects, such as chest and throat tightness, numbness, tingling, anxiety,
etc. (Ferrari and Saxena, 1995; Mathew, 1997).
Ultimately disappointing, none of the triptan drugs seems to exert any
benefit on the frequency of migraine incidence, unlike dihydroergotamine,
which has degree of prophylactic benefit.
Thus, it is the author's contention that this group of agents, though
impressive, may represent somewhat of a "therapeutic dead end." Especially
considering the large percentages of migraineurs who either fail to respond
to the triptans, or can not tolerate them, there seems to be definite need
for alternative treatment agents.
The author believes that the issue of medical marijuana, and its possible
role in migraine treatment deserves proper scientific examination, both
biochemically and clinically.
Results of controlled clinical trials may be valuable for migraineurs
andprofessionals 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).
The available evidence seems to suggest that smoked Cannabis would be a far
safer alternative than butorphanol nasal spray (Stadol-NS), which,
heretofore, has been an unscheduled drug approved in the U.S.A. for
migraine treatment despite its addictive potential and unfavorable side
effect profile (Fisher and Glass, 1997).
Conclusions:
- Cannabis, whether ingested, or smoked, has a long history of reportedly
safe and effective use in the treatment and prophylaxis of migraine.
- Cannabis has a mild but definite analgesic effect in its own right.
- Cannabis seems to affect nociceptive processes in the brain, and may
interact with serotonergic and other pathways implicated in migraine.
- Cannabis is reportedly an effective anti-emetic, a useful property in
migraine treatment.
- Cannabis, even when abused, has mild addiction potential, and seems to
be safe in moderate doses, particularly under the supervision of a physician.
- Cannabis' primary problem as a medicine lies in its possible
pulmonaryeffects, which seem to be minimal in occasional, intermittent use.
- Cannabis when inhaled, is rapidly active, obviates the need for
gastrointestinal absorption (impaired markedly in migraine), and may be
titrated to the medical requirement of the patient for symptomatic relief.
- Cannabis delivered by pyrolysis in the form a marijuana cigarette, or
"joint," presents the hypothetical potential for quick, effective
parenteral treatment of acute migraine.
In closing, a quotation seems pertinent (Schultes, 1973):
There can be no doubt that a plant that has been in partnership with man
since the beginnings of agricultural efforts, that has served man in so
many ways, and that, under the searchlight of modern chemical study, has
yielded many new and interesting compounds will continue to be a part
ofman's economy. It would be a luxury that we could ill afford if we allowed
prejudices, resulting from the abuse of Cannabis, to deter scientists from
learning as much as possible about this ancient and mysterious
plant.
Acknowledgements:
The author would like to thank the following individuals:
- Rick Doblin and Sylvia Thiessen of the Multidisciplinary Association for
Psychedelic Studies (MAPS), for financial support, and continued advice and
suggestions.
- Paulette Cote of Western Montana Clinic Library, and the
Inter-Library Loan Department at the Mansfield Library of the University of
Montana for wonderful service in locating obscure references.
- Drs. Tod Mikuriya and Lester Grinspoon for provision of books, suggestions and
encouragement.
- Drs. Keith Parker and Vernon Grund of the Department
ofPharmacy, University of Montana for their guidance and good sense.
- Drs. Varro Tyler and Dennis McKenna for their inspiration and the confidence
they engendered. Dr. Donald Abrams for his continuing efforts in pursuit of
medical indications for Cannabis. The Herbal Research Foundation and NAPRALERT for
assistance on ethnobotanical information.
- Dr. Samir Ross for his initial guidance on my inquiries about experimental research on cannabis.
- Marie-Josie Thibault, Deborah Somerville, and Penny King for their
faithfulness and "morale support."
- Ultimately, to Dr. Mark Russo, for reasons he alone will understand.
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