Cannabis for migraine treatment: the once and future prescription?
An historical and scientiﬁc review
Department of Neurology, Western Montana Clinic, 515 West Front Street, Missoula, MT 58907-7609, USA
Accepted 26 January 1998
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. 1998 International Association for the Study of Pain.
Published by Elsevier Science B.V.
Keywords: Migraine; Headache; Cannabis; Marijuana; Dronabinol; Ethnobotany
One of the basic tenets of medical history is that remedies
fall in and out of favor. Once supplanted, most pharmaceu-
ticals 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. Pro-
blems with quality control and an association with per-
ceived 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 medi-
cal 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
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
2. Historical and ethnobotanical usage of Cannabis in
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 convin-
cing 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 documen-
ted 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 Pe
Pain 76 (1998) 3–8
0304-3959/98/$19.00 1998 International Association for the Study of Pain. Published by Elsevier Science B.V.
* Tel.: +1 406 3297238; fax: +1 406 3297453;
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 She
ˆn-nung in the third mil-
lenium BC. The text noted that the plant fruits ‘if taken in
excess will produce hallucinations’ (literally ‘seeing dev-
ils’) (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 (Darmsteter, 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,
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,
O’Shaughnessy introduced the medical use of Cannabis
indica, or ‘Indian hemp’, to the West in 1839 (Walton,
1938; Mikuriya, 1973). 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. Propo-
nents 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, and others (Wal-
ton, 1938; Mikuriya, 1973). Cannabis was included in the
mainstream pharmacopeias in Britain and America for this
As late as 1915, Sir William Osler, the acknowledged
father of modern medicine, stated of migraine treatment
(Osler and McCrae, 1915), ‘Cannabis indica is probably
the most satisfactory remedy. Seguin recommends a pro-
longed 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 adher-
ents for a variety of medical indications, throughout the
early decades of the twentieth century. In 1938 Robert Wal-
ton 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 mari-
juana illegal in the USA 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 12
major authorities on its efﬁcacy for migraine, and only
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 ergo-
tamine tartrate, which remains in the migraine armamentar-
ium, some 55 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
In the 1960s 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 ben-
eﬁts on their maladies.
3. 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 super-
ior to ergotamine tartrate and aspirin.
One subsequent study of Cannabis pertained to pain tol-
erance in an experimental protocol (Milstein et al., 1975). A
statistically signiﬁcant increase in pain threshold was
observed after smoking Cannabis in both naive (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 5 h after ingestion of 20
4E. Russo / Pain 76 (1998) 3–8
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 1980s more comprehensive data on pharmacologi-
cal 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 Bar-
nett, 1984). Additionally, experimental subjects were able to
distinguish the potency of the various samples with accu-
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 second-
ary 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 ﬁnd-
ings 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-naive vs. 23% in experience smokers.
Oral bioavailability for THC was only about 6%, and
onset of effects was not seen for 30–120 min.
Smoking of massive Cannabis doses daily for a pro-
longed period produced lower intraocular pressure, serum
testosterone levels, and airway narrowing, but no chromo-
somal 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, 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 withdra-
wal 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 mari-
juana smoking were followed by migraine attacks. One
patient noted subsequent remission of headaches with epi-
sodic marijuana use, while conventional drugs successfully
treated the others. The author hypothesized that THC’s per-
ipheral vasoconstrictive actions in rats, or its action to mini-
mize 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 reclas-
sify 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 render-
ing his ruling (Young, 1988). Although a medical indication
of marijuana for migraine was not considered, its use was
approved as an anti-emetic, an anti-spasticity drug in multi-
ple sclerosis and paraplegia, while its utilization in glau-
coma 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 10
of 11 preferred oral THC to placebo. These results call into
serious question the plausibility of true blinding with pla-
cebo 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, arachido-
nylethanolamide, 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 pre-
liminary 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 ago-
nists on rat serotonin type 3 (5-HT
) receptors was demon-
strated (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
E. Russo / Pain 76 (1998) 3–8
intensiﬁed the public debate on medical beneﬁts of mari-
juana. In 1993, a book entitled Marihuana: The Forbidden
Medicine (Grinspoon and Bakalar, 1993) examined a vari-
ety of claims for ailments treated by marijuana, and includ-
ed an entire section on migraine. One clinical vignette dis-
cussed at length the medical odyssey of a migraineur
through failures with standard pharmaceuticals, and ulti-
mate preference for small doses of smoked marijuana for
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 pub-
lished a supportive commentary in 1995 (Grinspoon and
Bakalar, 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 theo-
retical 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 Canna-
bis use. In the summary, it states the following acute effects:
Anxiety, dysphoria, panic and paranoia, especially in
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 canna-
bis 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 medi-
cine’. 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 to
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 attesta-
tions of efﬁcacy for a variety of indications.
Various investigators have examined the roles of differ-
ent 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 standar-
dized 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.
Despite the development of serotonin 1D-agonist medi-
cations, 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 US$1.2 to $17.2 billion
annually in the USA in terms of lost productivity (Lipton
and Stewart, 1993).
In 1990 studies were published outlining the biochemical
basis of migraine treatment in serotonin receptor pharma-
cology (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
analogs are ineffective when administered in the ‘aura
phase’ of classic migraine (Ferrari and Saxena, 1995). Addi-
tionally, headache recurrence after ‘triptan’ 5-HT
agents is a not infrequent occurrence. Unfortunately, repe-
titive dosing, and development of agents with longer half-
lives does not seem to avert the issue (Ferrari and Saxena,
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 cen-
tral nervous system penetration has not necessarily
6E. Russo / Pain 76 (1998) 3–8
improved efﬁcacy, but does increase the likelihood of side
effects, such as chest and throat tightness, numbness, tin-
gling, 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
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 per-
centages of migraineurs who either fail to respond to the
triptans, or cannot 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 effec-
tively 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 USA for migraine treatment despite its addictive
potential and unfavorable side effect proﬁle (Fisher and
1. Cannabis, whether ingested or smoked, has a long his-
tory of reportedly safe and effective use in the treatment
and prophylaxis of migraine.
2. Cannabis has a mild but deﬁnite analgesic effect in its
3. Cannabis seems to affect nociceptive processes in the
brain, and may interact with serotonergic and other path-
ways 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 poten-
tial, 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 require-
ment 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
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 agricul-
tural efforts, that has served man in so many ways,
and that, under the searchlight of modern chemical
study, has yielded many new and interesting com-
pounds 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 Can-
nabis, to deter scientists from learning as much as
possible about this ancient and mysterious plant.
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 Grin-
spoon for provision of books, suggestions and encourage-
ment. Drs. Keith Parker and Vernon Grund of the Depart-
ment of Pharmacy, University of Montana for their gui-
dance 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-Jose´e Thibault, Deborah Somerville, and
Penny King for their faithfulness and ‘moral support’. Ulti-
mately, to Dr. Mark Russo, for reasons he alone will under-
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