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.
Keywords: migraine, headache, Cannabis, marijuana, dronabinol, ethnobotany
Ethan Russo, M.D.
Address:
Department of Neurology
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 Pˆn-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 Shˆn-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 na‹ve (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 many of the elderly
Cannabis-naive 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‹ve 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
o anxiety, dysphoria, panic and paranoia, especially in naive users;
o cognitive impairment, especially of attention and memory, for the
duration of intoxication;
o psychomotor impairment, and probably an increased risk of accident if
an intoxicated person attempts to drive a motor vehicle, or operate
machinery;
o an increased risk of experiencing psychotic symptoms among those who
are vulnerable because of personal or family history of psychosis;
o an increased risk of low birth weight babies if cannabis is used
during pregnancy.
In a current review of over 65,000 patient records in an HMO (Sidney et
al., 1997), little effect of smoked Cannabis was seen on morbidity and
mortality of non-AIDS patients.
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
estimated 14% 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
and 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).
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:
1) Cannabis, whether ingested, or smoked, has a long history of
reportedly safe and effective use in the treatment and prophylaxis of
migraine.
2) Cannabis has a mild but definite analgesic effect in its own right.
3) Cannabis seems to affect nociceptive processes in the brain, and may
interact with serotonergic and other pathways implicated in migraine.
4) Cannabis is reportedly an effective anti-emetic, a useful property in
migraine treatment.
5) Cannabis, even when abused, has mild addiction potential, and seems to
be safe in moderate doses, particularly under the supervision of a
physician.
6) Cannabis' primary problem as a medicine lies in its possible pulmonary
effects, which seem to be minimal in occasional, intermittent use.
7) 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.
8) 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 of
man'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 of Pharmacy, 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-JosŠe
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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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/).
Western Montana Clinic
515 West Front Street
Missoula, MT 58907-7609
U.S.A.
Phone: (406) 329-7238
FAX: (406) 329-7453
E-Mail: ptm5739@montana.com