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The health and psychological consequences of cannabis use chapter 8
8. The therapeutic effects of cannabinoids
8.1 Historical background
Cannabis has had a long history of medical and therapeutic use in
India and the Middle East (Grinspoon and Bakalar, 1993; Mechoulam,
1986; Nahas, 1984) where it has been variously used as an analgesic,
anti-convulsant, anti-spasmodic, anti-emetic, and hypnotic. Cannabis
was introduced to British medicine in the mid-nineteenth century by
O'Shaugnessy (1842) who had gained clinical experience with the drug
while an Army surgeon in India (Mechoulam, 1986; Nahas, 1984). He
recommended its use for the relief of pain, muscle spasms, and
convulsions occurring in tetanus, rabies, rheumatism and epilepsy
(Nahas, 1984). Partly as the result of his advocacy, cannabis came to
be widely used as an analgesic, anti-convulsant and anti-spasmodic
throughout the middle part of the 19th century in Britain and the USA.
The medical use of cannabis declined around the turn of the present
century. Because the active constituents of cannabis were not isolated
until the second half of the twentieth century, cannabis continued to
be used in the form of natural preparations which varied in purity
and, hence in effectiveness. The use of cannabis was largely
supplanted by other pharmaceutically purer drugs, which could be given
in standardised doses to produce more dependable effects. These
included the opiates, aspirin, chloral hydrate, and the barbiturates
(Mechoulam, 1986; Nahas, 1984). In the early part of the century, the
medical use of such crude cannabis preparations was further
discouraged by laws which treated cannabis as a "narcotic" drug and
severely restricted its availability. It finally disappeared from the
American pharmacopoeia in the early 1940s after the passage of the
Marijuana Tax Act (Grinspoon and Bakalar, 1993), although it continued
to be used in Australia into the 1960s (Casswell, 1992).
THC, the major psychoactive ingredient of cannabis, was not isolated
until 1964 (Goani and Mechoulam, 1964), shortly before cannabis
achieved widespread popularity as a recreational drug among American
youth. Its widespread recreational use, and its symbolic association
with a rejection of traditional social values, undoubtedly hindered
pharmaceutical research into its therapeutic uses. Consequently, the
rediscovery of some of its traditional therapeutic uses was largely
serendipitous, as was the discovery of some newer uses. For example,
its value as an anti-emetic agent in the treatment of nausea caused by
cancer chemotherapy seems to have been rediscovered by young adults
who had used cannabis recreationally prior to undergoing chemotherapy
for leukemia (Grinspoon, 1990).
From the mid-1970s some clinical research on the therapeutic value of
cannabis and cannabinoids was undertaken. On the whole, however, this
research has been very thin and uneven, and, consequently, many of the
claims for the therapeutic efficacy of cannabinoids rely heavily, and,
in the case of rare medical conditions, solely upon anecdotal
evidence, that is, the testimonies of individuals who claim to have
derived medical benefit from its use (e.g. Grinspoon and Bakalar,
1993; Randall, 1990), and small numbers of cases reported by
physicians (e.g. Consroe et al, 1975; Meinck et al, 1989).
Evidence will be reviewed for the best-supported therapeutic uses of
cannabinoids. The review begins with the evidence on the effectiveness
of cannabinoids as anti-emetic drugs for nausea caused by cancer
chemotherapy, and as agents to control intra-ocular pressure in
glaucoma. Briefer reviews are provided of the evidence in favour of
other putative therapeutic uses of cannabinoids which are less well
supported by clinical evidence, chief among which are its uses as an
anti-convulsant, an anti-spasmodic, and an analgesic agent. The value
and limitations of the largely anecdotal evidence of efficacy in these
latter conditions will also be briefly considered. The review will
include a discussion of the controversy in the United States about
"marijuana rescheduling" which has coloured much recent discussion of
the issue. This controversy concerns the vexatious issue of whether
smoked cannabis should be available for medical use in addition to
synthetic cannabinoids such as THC.
8.2 Cannabinoids as anti-emetic agents
Profound nausea and vomiting can be such serious complications of
chemotherapy and radiotherapy for cancer that patients may discontinue
potentially life-saving treatment (Institute of Medicine, 1982).
Although various types of drugs (e.g. the phenothiazines) have been
shown to be effective in controlling nausea and vomiting in cancer
patients, substantial minorities of patients do not benefit from these
drugs. The seriousness of the problem of chemotherapy-induced nausea,
and the incomplete success of existing treatments, prompted
oncologists in the late 1970s and early 1980s to take a particular
interest in the anti-emetic properties of cannabinoids (Institute of
Medicine, 1982).
8.2.1 Clinical trials
One of the earliest trials of the effectiveness of THC as an
anti-emetic was prompted by patient reports that smoking marijuana
relieved nausea and vomiting (Sallan et al, 1975). In this study, 22
patients (10 males and 12 females, average age 30 years) with a
variety of neoplasms were studied. In 20 patients, the nausea and
vomiting had proven resistant to existing anti-emetic drugs. A
randomised placebo-controlled trial with crossover was used, in which
patients were randomly assigned to receive oral THC (10mg per m2) and
placebo in one of four different orders (THC-placebo-THC; THC-
placebo-placebo; placebo-THC-placebo; placebo-THC-THC). Outcome was
assessed by grading patients' self-reports of nausea and vomiting
after THC and placebo into three categories: complete response if
there was vomiting after placebo but not after THC; partial response
if there was a greater than 50 per cent reduction in nausea and
vomiting after THC compared to placebo; and no response if there was a
less than 50 per cent reduction in nausea and vomiting.
Ten patients completed all three courses of THC and placebo and
vomited on at least one trial. After excluding one trial because of a
variation in the chemotherapy dose, there were 29 trails available for
analysis, 14 of placebo and 15 of THC. All 14 placebo trials resulted
in no response, while in the 15 THC trials there were five complete
responses, seven partial responses, and three no responses. This
difference was statistically significant when full and partial
responses were combined. Most patients (13/16) reported a "high" after
receiving THC, an experience which was correlated with the anti-emetic
effect. The most common side-effect was somnolence which curtailed
activities for two to six hours in a third of patients. Only two
patients experienced any symptoms of toxicity, (both after receiving
20mg doses of THC), namely, visual distortions and hallucinations and
depression lasting several hours. Sallan et al reported "preliminary"
observations from several patients that smoking marijuana produced an
equivalent anti-emetic effect to oral THC.
A trial by Chang et al (1979) largely supported the findings of Sallan
et al. In this study 15 patients with osteogenic sarcoma (10 males and
five females, average age 24 years) served as their own controls in
the course of monthly high dose methotrexate therapy. They were
assigned to receive three THC and three placebo trials in randomised
order during six treatment sessions. THC (10mg per m2 of body area)
and placebo were administered orally five times at three hourly
intervals, beginning two hours before chemotherapy. If the patients
vomited, the remaining doses of either THC or placebo were
administered by smoking a cigarette using a standardised smoking
technique. The effect of THC and placebo were assessed by nursing
staff who rated various endpoints (e.g. number of vomiting and
retching episodes, volume of emesis, degree and duration of nausea)
without being aware of which treatment patients had received. Patient
response was graded into three categories: excellent (greater then 80
per cent reduction after THC by comparison with placebo in each of
these endpoints); fair (greater than 30 per cent and less than 80 per
cent reduction), and no response (less than 30 per cent reduction).
The results showed that eight patients had an excellent response, six
a fair response, and one had no response. On all endpoints THC
produced a statistically significant reduction in nausea and vomiting
by comparison with placebo. There was also a dose-response
relationship between blood levels of THC and the incidence of nausea
and patient reports of feeling "high". Generally, higher THC blood
levels were achieved when marijuana was smoked than when THC was taken
orally. There were few side effects reported, with sedation being the
most common (12/15 patients). Four patients experienced five dysphoric
reactions in the course of 281 THC drug doses (2 per cent), none of
which lasted more than 30 minutes, and all of which were successfully
managed with simple reassurance.
In a second phase of the study, four patients who had an excellent
response to THC in the first phase were retested under double-blind
conditions using two placebo trials in the next 10 treatments. A small
number of patients who had a fair response were also studied using an
increased dose of THC. All patients showed a reduction in the average
anti-emetic benefit of THC, decreasing from excellent to fair in the
case of previous excellent responders, and from fair to no response in
the case of the fair responders. Chang et al hypothesised that the
decline in effect reflected either the development of tolerance to the
effects of THC, or the development of conditioned nausea and vomiting
that was resistant to the anti-emetic effects of THC.
Since these early studies, a large number of controlled clinical
studies have been conducted which compared the effectiveness of THC
with either a placebo or with other anti-emetic drugs (see Carey et
al, 1983; Poster et al, 1981; Levitt, 1986 for reviews). The results
of this literature have sometimes been unfairly described as
"confused" (e.g. Carey et al, 1983; Nahas, 1984). This description
betrays an unreasonably high expectation of the consistency of results
from studies which have generally used small samples of heterogenous
patients who have received various forms of chemotherapy. It also
ignores the fact that the cross-over studies comparing the anti-emetic
effects of THC with placebo have generally reported greater
anti-emetic effects for THC than placebo (Poster et al, 1981); the
single exception to this finding was a study which had a sample size
of only eight patients.
Comparisons of the effectiveness of oral THC with that of existing
anti-emetic agents have been less consistent than the results of
comparisons with placebo. Nonetheless, the results have generally
indicated that THC is at least equivalent in effectiveness to the
widely used anti-emetic drug prochlorperazine (Carey et al, 1983;
Levitt, 1986). The inconsistencies in this case arise because some
studies have shown THC to be superior, probably because of the
practice in some trials of enlisting patients whose nausea had
previously proven resistant to prochlorperazine (Carey et al, 1983).
The equivalence of THC and prochlorperazine has been supported by the
results of one of the largest and best conducted studies (Ungerleider
et al, 1982). In this study 214 patients with a variety of forms of
cancer (carcinomas, sarcomas, lymphomas and leukemias) were recruited
if they had already undergone chemotherapy and experienced nausea and
vomiting, or they were to receive a form of chemotherapy which had a
high emetic potential. Patients were randomly assigned to receive a
paired trial of either oral THC followed by prochlorperazine or vice
versa. The dose of THC was dependent on body surface area (7.5mg if
less than 1.4m2, 10mg for 1.4 to 1.8m2, and 12.5mg for greater than
1.8m2). Separate analyses were conducted on three groups of patients:
patients who received their cancer chemotherapy on a single day some
weeks apart (N=98); patients who received their chemotherapy on a
daily basis over several successive days (N=41); and patients who
discontinued the trial after a single episode of either THC or
prochlorperazine. Outcomes were patient self-ratings of nausea and
vomiting, and a variety of mood states and behaviours.
The results showed that there "were no statistically significant
differences in the anti-nausea/anti-emetic effect of THC and
prochlorperazine" (p640) in any of the three patient groups, even
though there were differences between patients in the single- and
multiple-day chemotherapy regimens in the time course of the nausea.
There were differences in mood and behaviour between the THC and
prochlorperazine trials, with patients reporting greater impairment of
concentration and less social interaction after receiving THC. There
were also more side effects from THC than prochlorperazine, with
sedation, sleepiness and mental clouding being the most common. There
was no difference in the frequency of panic attacks between the two
drugs. Despite these differences in side effects there was a small
patient preference in favour of THC as an anti-emetic, with 41 per
cent experiencing less nausea on THC, 31 per cent experiencing less
nausea on prochlorperazine, and 29 per cent reporting no difference in
effectiveness. The effectiveness of THC was not related to age or
prior experience with marijuana, but it was related to the experience
of side effects, with patients experiencing them reporting less
nausea.
Given the wide variety of patients who have been studied in terms of
age and type of cancer, the wide variety of chemotherapeutic agents
that have been used to treat their cancers, and the variety of
different anti-emetics with which THC has been compared, the fact that
findings of these studies are generally positive for THC is more
impressive than the apparent differences in outcome. The positive
results from the controlled trials also seem to be borne out by
clinical experience with cannabinoids in managing cancer patients. A
recent survey of a large sample of American oncologists, for example,
found that 44 per cent of oncologists had recommended marijuana to at
least one cancer patient, and 64 per cent of these physicians reported
that it was successful controlling nausea in at least half of their
patients. Overall, just under half of the oncologists in the sample
(44 per cent) believed that cannabinoids could be safely used in the
treatment of nausea caused by chemotherapy and radiotherapy (Dobin and
Kleiman, 1991). A similar proportion (48 per cent) reported that they
would prescribe marijuana for their patients if it was legal.
The general conclusion on the available literature is that THC is
superior to placebo, and equivalent in effectiveness to other
widely-used anti-emetic drugs, in its capacity to reduce the nausea
and vomiting caused by some chemotherapy regimens in some cancer
patients. There are a number of issues that remain to be resolved in
deciding upon the clinical role of cannabinoids as anti-emetic agents
in cancer chemotherapy. These issues include: the types of nausea
against which it may be most effective, and hence the types of
patients for which they are most appropriately prescribed; the degree
of patient tolerance of the psychotropic side effects of THC and other
cannabinoids; the potential seriousness of possible THC induced
immunosuppression in patients who are already immunologically
compromised; the most effective dosing schedules for THC as an
anti-emetic; the potential use of THC in combination with other
anti-emetic drugs; and the extent to which the motivation for the use
of THC may have been reduced by the availability of newer anti-emetic
drugs that are more effective than prochlorperazine (the main
anti-emetic drug in the 1980s).
8.2.2 Which patients?
Which patients with what types of nausea are the most suitable for
treatment with cannabinoids as anti-emetics? Patients with various
forms of cancer have been the most extensively investigated patient
group, but the numbers of different types of cancer have been too
small to allow convincing analyses of differences in patient response.
The same point can be made about types of chemotherapy regimens; they
have varied widely in these studies, and have often not been reported,
but there has been no systematic analysis of the effectiveness of
cannabinoids in controlling emesis produced by different agents. It is
uncertain to what extent the cannabinoids may be effective against
nausea from other causes. The mechanisms that produce nausea are not
well understood but there are believed to be one or more protective
mechanisms located in the brain stem that can be triggered by a
variety of emetic agents. This raises the possibility that
cannabinoids may be therapeutically useful against nausea from a
variety of causes.
8.2.3 Side effects
The psychoactive effects of cannabis which are prized by recreational
users - euphoria, relaxation, drowsiness - are not always welcomed by
older patients, most of whom are cannabis-naive. In some studies a
substantial minority of such patients have discontinued the use of THC
because of the unwelcome dysphoria and somnolence (Levitt et al,
1986). This has not been a universal experience, so further research
is required to discover to what extent this has been the result of
unnecessarily large doses, or poor patient preparation for these
effects, and failure to adequately manage them by reassurance. What
does seem to be the case is that the experience of some psychological
effects of THC, including the "high", is necessary for the occurrence
of a clinically significant anti-emetic effect. This fact has led to
the search, so far unsuccessful, for cannabinoid derivatives of THC
which possess its anti-emetic properties but not its psychoactive
ones. The recent discovery of the cannabinoid ligand and receptor, and
receptor subtypes (see pp7-8) has encouraged researchers to believe
that this may be an achievable goal (Iversen, 1993).
A potentially more serious side effect of therapeutic THC is its
possible immunosuppressive effect. Any such effect would limit its use
as an anti-emetic in the treatment of cancer, since cancer patients
experience immune suppression as a side effect of their treatment.
There are several reasons why this may be less serious an issue that
it seems at first glance. First, there are doubts about the existence
of any immunosuppressive effect of cannabinoids (see Section 6.2 on
the immune system, pp62-68), and the effect is small in those studies
which report one. Second, the clinical significance of any such
effects is doubtful in the use of THC in cancer chemotherapy. Such use
would be intermittent, and relatively short-term, and the possible
gain in increased life expectancy from being able to complete a course
of cancer chemotherapy is such that most patients would be prepared to
take the risk, in the same way that they chose to undergo the highly
toxic chemotherapy in the first place.
8.2.4 Unresolved clinical issues
If THC has a place in the management of nausea from cancer treatment
(Poster et al, 1981), and perhaps other causes, a number of clinical
issues remain to be resolved (Levitt, 1986). Foremost among these is
the best way in which to administer the drug. Should it be given well
in advance of treatment at low doses to ensure a stable blood level,
or should it be given in larger doses shortly before chemotherapy or
radiotherapy? This issue has not been systematically studied (Levitt,
1986).
An additional question is whether there is any clinical benefit to be
derived from combining THC with existing anti-emetic agents. There is
suggestive evidence that there might be, since the mechanisms of
action, while not well understood, appear to be different, raising the
possibility that there may be positive synergistic effects from the
combination of THC and other anti-emetics. One single-blind study of
the combination of dronabinol and prochlorperazine, for example,
suggested that the combination of these drugs may have a superior
anti-nausea effect to either drug used alone (Plasse et al, 1991).
Clearly, more research is warranted on this issue, especially as it
may enable cannabinoids to be used as anti-emetics at lower doses with
fewer unwanted psychotropic effects.
It seems surprising that the desirability of undertaking research on
dosing and combined use of cannabinoids was highlighted by Poster et
al in 1981 and by the Institute of Medicine in 1982. Yet very little
research has been done, and THC has not been routinely incorporated
into the management of nausea caused by cancer chemotherapy. One of
the likely reasons has been the American controversy about the
rescheduling of marijuana under the Controlled Substances Act, which
some argue has discouraged clinical research on cannabinoids (see
below). Another reason has been that the motivation for further
research on the anti-emetic properties of THC has been removed by the
recent development of newer anti-emetic drugs which are superior to
prochlorperazine (Iversen, 1993), the "gold standard" drug when the
major controlled trials were conducted on cannabis in the 1970s and
1980s. In the absence of trials comparing THC with these newer drugs,
its comparative efficacy is unknown, although given its approximate
equivalence to prochlorperazine it is likely to be inferior to the
newer drugs.
8.3 Cannabinoids as anti-glaucoma agents
Glaucoma is the leading cause of blindness in the United States,
affecting two million people and producing 300,000 new cases each year
(Adler and Geller, 1986). It is a condition "which is generally
characterised by an increase in intraocular pressure ... that
progressively impairs vision and may lead to absolute blindness"
(Adler and Geller, 1986, p54). Although its causes are not understood,
it is believed to involve an obstruction to the outflow of the aqueous
humour in the eye leading to a gradual increase in intraocular
pressure (IOP) which, if untreated, may damage the optic nerve,
resulting in blindness. Its incidence increases over the age of 35,
especially among individuals who are myopic (i.e. short-sighted).
Although various drugs are available which reduce IOP, all possess
unwanted side-effects and patients may become tolerant to their
therapeutic effects.
The effects of cannabis in reducing IOP were discovered
serendipitously by researchers and patients in the early and middle
1970s. Hepler and his colleagues (1971, 1976) observed a substantial
decrease in IOP while researching the effects of cannabis intoxication
on pupil dilation. They demonstrated that both cannabis and oral THC
produced substantial reductions in IOP in both normal volunteers and
patients with glaucoma (Hepler and Petrus, 1976; Hepler et al, 1976).
Subsequent research identified THC as the agent responsible for
producing this effect (Adler and Geller, 1986).
Around the same time, patients with glaucoma who had used cannabis
recreationally also discovered its therapeutic effects. One such
patient, Robert Randall, used cannabis daily to control his glaucoma.
When arrested for possession and cultivation of cannabis, he
successfully used the defence of "medical necessity" arguing, with the
support of his physicians, that he would go blind if he stopped his
cannabis use. He subsequently was given legal access to cannabis for
medical purposes (Randall Affidavit, in Randall, 1988).
Although there have been a number of case reports of the successful
use of cannabis in the management of glaucoma (e.g. Grinspoon and
Bakalar, 1993; Randall, 1990), there have not been any controlled
clinical studies of its effectiveness and safety in the long-term
management of glaucoma. Informed clinical opinion has been that THC is
an effective anti-glaucoma agent when used acutely, but there are
doubts about its effectiveness with chronic use because of the
development of tolerance to its effects on IOP (Jones et al, 1981).
Ophthalmologists who are opposed to the clinical use of THC point to a
number of major disadvantages. First, because THC is not
water-soluble, it cannot, unlike other anti-glaucoma agents, be
applied topically to the eye to ensure that enough is absorbed to
produce a clinically significant reduction in IOP. Second, as a
consequence, THC must be absorbed systemically in order to produce a
therapeutic effect on IOP, which means that patients must experience
the psychoactive effects of THC in order to derive its therapeutic
benefits against glaucoma. Third, because glaucoma is a chronic
condition, THC or cannabis would need to be taken in substantial doses
on a daily basis over long periods of time, if not for the remainder
of adult life. There has been an understandable concern about the
health risks of chronic daily cannabis use (e.g. Hepler, 1990;
American Academy of Ophthalmology, 1990).
The position adopted by the American Academy of Ophthalmology has been
to insist that cannabis has no accepted medical use in the management
of glaucoma, and cannot have such medical use until a large controlled
trial has been conducted into its safety and effectiveness in daily
chronic use. There has been no evidence that the Academy has any
interest in, or has given any encouragement to, the conduct of such a
trial. Consequently, its position is that THC and other cannabinoids
should not be used be in the management of glaucoma.
A contrary position has been taken by Randall, who has argued that
patients should be allowed to make the choice between the uncertain
health risks of chronic cannabis use and the more certain risks to
sight of poorly controlled glaucoma:
"People with life- and sense-threatening diseases are routinely
confronted by stark choices ... [between] the devastating consequences
of a debilitating, progressive disease ... [and] often highly damaging
biological and mental consequences of the toxic chemicals required to
check the progression of disease. .. Viewed in this medical context,
marihuana is more benign and far less damaging that the synthetic
toxins routinely prescribed by physicians" (cited in Grinspoon and
Bakalar, 1993, p153)
8.4 Cannabinoids and neurological disorders
8.4.1 Anti-convulsant
Historically one of the commonest medical uses of cannabis
preparations has been as an anti-convulsant. O'Shaughnessy (1842), for
example, recommended the use of cannabis to control seizures in
epilepsy, tetanus and rabies (Nahas, 1984). Animal studies have
provided some support for this use in showing that THC has dual
effects on convulsions, i.e. they can produce convulsions in
susceptible animals, and suppress the maximum severity of convulsions
from a variety of causes, while cannabidiol (CBD) appears to be a
potent anti-convulsant (Chesher and Jackson, 1974; Consroe and Snider,
1986; Institute of Medicine, 1982).
Despite this animal evidence, there is very limited evidence on the
therapeutic effects of cannabinoids in humans with epilepsy. There are
a small number of case studies of individuals with epilepsy in which
the recreational use of cannabis appeared to enhance the
anti-convulsant effects of more traditional anti-convulsant medication
(e.g. Consroe et al, 1975; Grinspoon and Bakalar, 1993). There is a
single randomised placebo controlled study of the administration of
CBD in 15 patients with epilepsy that was not well controlled by
conventional anti-convulsants. Four of the eight patients who received
CBD in addition to their usual anti-convulsant drugs were free of
seizures throughout the study period, and three were improved. By
contrast, only one out of seven patients in the placebo condition
showed any clinical improvement (Cunha et al, 1980). Despite this
suggestive evidence of efficacy in epilepsy, CBD has not been widely
used in clinical management. Perhaps this is not surprising given the
absence of evidence of its efficacy, the existence of other effective
anti-convulsant drugs, and concerns about the safety of chronic use in
the management of a chronic disease. It is perhaps more surprising
that there has been no further research on the anti-convulsant
properties of CBD, especially as it has no psychoactive side effects
(Nahas, 1984).
8.4.2 Anti-spasmodic
Cannabinoids have been used in an empirical way in the management of
some patients with movement disorders, a variety of syndromes that
have in common a deficit in non-pyramidal motor control function,
which is expressed in usually one or more of the non-epileptic,
abnormal involuntary movements, such as those found in Parkinson's
disease, Huntington's disease, multiple sclerosis, and spasticity.
Although a number of drugs may be of benefit in the management of
these conditions, they are not always effective, and may produce
troublesome side-effects (Consroe and Snider, 1986).
There has been some animal evidence which indicates that THC and its
analogues produce a broad spectrum of neurological effects, which
include alterations in motor function, and changes in muscle tone and
reflexes. The acute motor effects in normal humans - ataxia,
tremulousness and subjective weakness - also suggest a potential for
therapeutic effects in some movement disorders (Consroe and Snider,
1986).
The evidence that cannabinoids have therapeutic effects in patients
with movement disorders is largely anecdotal. Grinspoon and Bakalar
(1993), for example, present four case histories of individuals with
multiple sclerosis whose condition improved while they smoked
marijuana, and deteriorated after they stopped smoking. Meinck et al
(1989) report a case history of a young man with multiple sclerosis
with severe limb and gait ataxia who complained of erectile impotence.
After smoking marijuana his gait improved sufficiently to be able to
walk unaided, and he was able to achieve and sustain an erection. When
cannabis was withdrawn under medical supervision, the patient's motor
function deteriorated to the point where he was unable to walk without
assistance.
There has been one controlled study by Clifford (1983) who examined
the effects of THC on tremor in eight patients (four male and four
female) with advanced multiple sclerosis who had ataxia and tremor.
Five patients reported subjective benefit from THC and there was
objective evidence of benefit in two of these cases. Single-blind
placebo challenge in these cases produced evidence that their clinical
condition deteriorated when given placebo and improved with the
reinstatement of THC.
Grinspoon and Bakalar (1993) described several case histories of
individuals with paraplegia and quadriplegia who reported that
cannabis use helped to reduce muscle spasm. The experiences of these
individuals were supported by similar reports obtained from a survey
of 43 individuals with spinal cord injuries, 22 of whom reported that
they used cannabis to control their muscle spasm.
The only controlled trial of a cannabinoid in a movement disorder has
been an evaluation of the effects of CBD on severity of chorea in
patients with advanced Huntington's disease (Consroe et al, 1991).
This study was prompted by the authors' observation that CBD had
improved the condition of an individual with Huntington's disease
(Sandyck et al, 1988). In this study 19 Huntington's patients were
enrolled in a double-blind controlled trial in which they received six
weeks administration of CBD or placebo in a cross-over design. The
outcome was the severity of chorea, as assessed by blind clinical
ratings, patient self-report, and a variety of measures of motor
function. Although the study had sufficient statistical power to
detect a relatively small clinical benefit, there was no evidence of
improvement in chorea on any of the clinical, self-report or motor
measures. In the light of Consroe et al's failure to replicate the
earlier favourable single case, further controlled trials are
warranted before any of the cannabinoids can be routinely used in
treating movement disorders.
8.5 Cannabinoids as anti-asthmatic agents
Smoked cannabis, and to a lesser extent oral THC, have an acute
bronchodilatory effect in both normal persons and persons with asthma
(Tashkin et al, 1975; Tashkin et al, 1976). Tashkin et al (1975), for
example, compared the bronchodilator effect of smoked cannabis with
that of a standard clinical dose of the bronchodilator isoproterenol
in relieving experimentally induced asthma in asthmatic patients. They
found that smoking a 2 per cent-THC cannabis cigarette produced a
bronchodilator nearly equivalent to that of a clinical dose of
isoproterenol.
Despite this early suggestion of a therapeutic effect in asthma,
cannabinoids have not been used therapeutically, nor have they been
extensively investigated as anti-asthmatic agents other than by
Tashkin and his colleagues (Tashkin, 1993). A major obstacle to
therapeutic use has been the route of administration. Oral THC
produces a smaller bronchodilator effect after a substantial delay,
and when used as an inhalant produces irritation and reflex
bronchoconstriction. Hence, smoking marijuana has been the most
dependable way of delivering a clinically effective dose of THC. There
is an understandable concern among clinical researchers that smoking
is an unsuitable mode of administering any drug, and an especially
inappropriate way to administer a drug to patients with asthma,
because it would inevitably involve the delivery of other noxious
chemicals that would nullify its therapeutic value in the short term,
and carry an increased risk of other respiratory disease and possibly
cancer in the long term (Tashkin, 1993). The unwanted psychotropic
effects from marijuana smoking have also been a barrier to its use as
an anti-asthmatic drug. Some investigators (e.g. Graham, 1986) have
nonetheless argued that the suitability of THC as a spray should be
further investigated because of the possible hazards of the chronic
use of the more widely-used beta-blocker antagonists. The recent
discovery of the cannabinoid receptor and ligand may prompt a
re-examination of this question.
8.6 Cannabinoids as analgesics
There is some animal evidence that THC has an analgesic effect which
operates via a different mechanism from that of the opioid drugs
(Segal, 1986). There is a small amount of human experimental studies
which have reported mixed evidence of an analgesic effect (Nahas,
1984). There has been little clinical evidence beyond historical use
for various forms of chronic pain, including migraine, dysmenorrhoea,
and neuralgia, and the small number of case histories of its use in
chronic pain, dysmenorrhoea, labour pain, and migraine reported by
Grinspoon and Bakalar (1993).
Only one double-blind controlled cross-over study has been reported.
This study compared the analgesic effect of THC and codeine in
patients with cancer pain (Noyes et al, 1975). The findings suggested
that 20mg of THC was of equivalent analgesic effect to 120mg of
codeine. However, neither drug produced substantial analgesia in these
patients, and the majority of patients found the psychotropic effects
of 20mg of THC sufficiently aversive that they discontinued its use.
Clearly, much more basic pharmacological and animal investigation is
required before cannabinoids or their derivatives have any clinical
use as analgesics. Nevertheless, such investigations may be worth
pursuing because of the dependence potential of the more potent opioid
analgesics, and the likelihood that any cannabinoid mediated analgesic
effect operates by a different mechanism to that of the opioids.
8.7 Other possible therapeutic uses
A variety of other therapeutic uses have been suggested, although few
have been investigated in any depth. In the late 1940s, for example,
there were some investigations of the therapeutic uses of the
euphoriant properties of cannabis, as a possible anti-depressant agent
in the form of synhexil, a synthetic cannabis analogue. The results in
one uncontrolled study were positive, but these were not replicated in
later studies using lower doses (Nahas, 1984; Grinspoon and Bakalar,
1993). None of these suggestions have been further investigated,
probably because of the potential for THC to produce dysphoric and
other unwanted psychotropic side effects.
8.8 Cannabis and AIDS
One of the areas of greatest contemporary interest in the therapeutic
uses of cannabinoids and cannabis has been their possible roles as an
anti-nausea agent, an appetite stimulant and an analgesic in patients
with AIDS (Randall, 1989). The development of this interest seems to
have replicated the earlier discovery of the anti-emetic effects of
cannabis in young cancer patients in the 1970s. AIDS patients often
experience nausea and weight loss, either while receiving cytotoxic
drugs to suppress HIV, or as a direct effect of the AIDS spectrum
diseases. Many patients have been recreational cannabis users, and so
have reported that the smoking of marijuana produces a diminution in
their nausea, an increased appetite, reduced pain, and general
improvements in well being. AIDS advocacy groups have accordingly
argued that marijuana should be made legally available to AIDS
patients (e.g. Randall, 1991).
So far the bulk of evidence for these therapeutic claims has been
provided by case reports (see Randall, 1989). There has been one small
uncontrolled study of 10 symptomatic AIDS patients which suggested
that dronabinol (synthetic THC) may be effective in reducing nausea
and stimulating appetite (Plasse et al, 1991). The evidence of its
anti-emetic properties in cancer patients seems to support its
potential application in AIDS treatment, and is deserving of further
investigation.
A potential concern with the use of cannabinoids in HIV positive
individuals and AIDS patients is the possible immunosuppressive
effects of cannabinoids. Although, as argued above, this effect is
likely to be small and of limited concern when used intermittently in
cancer patients, it is of potentially greater significance in AIDS
patients, since cannabis would be used regularly by patients with a
major immune system disorder. Even a small impairment in immunity may
have major consequences for HIV and AIDS affected individuals. Recent
epidemiological evidence does something to allay this concern. A large
prospective cohort study of HIV/AIDS in homosexual and bisexual men
recently failed to find any relationship between cannabis use, or any
other psychoactive drug use, and the rate at which HIV positive men
developed clinical AIDS (Kaslow et al, 1989). Nonetheless, the issue
of immunosuppression needs to be explicitly investigated in any
research which is undertaken into the therapeutic uses of cannabinoids
in the treatment of AIDS.
8.9 The limitations of anecdotal evidence
Much of the case for the therapeutic uses of cannabinoids as other
than anti-emetic agents depends upon anecdotal evidence from case
histories. Such evidence has justifiably come to be distrusted as
evidence of therapeutic effectiveness in clinical medicine, especially
in the case of chronic conditions which have a fluctuating course of
remission and exacerbation. In such diseases, it is difficult to
exclude alternative explanations of any apparent relationship between
the use of a drug (e.g. THC) and an improvement in a patient's
condition. Among the alternative explanations that are most difficult
to exclude in a single case or even a succession of single cases is
simple coincidence: that is, there may be no relationship between the
use of the drug and improvement; the apparent relationship between the
two may have arisen because the use of the drug preceded an
improvement in the patient's condition that would have occurred in its
absence. This is especially likely to occur in a chronic condition
with a fluctuating course. In addition, the well-known placebo effect
which is observed in many conditions may explain the apparent benefits
of a drug or other treatment. It is for these reasons that this review
has relied upon evidence from controlled clinical trials in appraising
the therapeutic uses of cannabinoids.
Grinspoon and Bakalar (1993) have attempted to defend anecdotal
evidence of therapeutic efficacy of cannabinoids. They argue that a
double standard has been used in the appraisal of the safety and
efficacy of cannabinoids: anecdotal evidence of harm has been readily
accepted while anecdotal evidence of benefit has been discounted.
Although at first glance "double standards" may seem to describe the
behaviour of the regulatory authorities, it is defensible to use
different standards of proof when evaluating the benefits and the
costs of therapeutic drugs. It is reasonable to err on the side of
caution by requiring stronger evidence of benefit from putatively
therapeutic drugs in order to ensure that the possible risks incurred
by their therapeutic use do not outweigh their benefits. Moreover,
this behaviour is not peculiar to the therapeutic appraisal of
cannabinoids; it is standard practice in the therapeutic appraisal of
all drugs. Medical practitioners are encouraged to report cases
histories of possible adverse effects of prescribed drugs. Such
reports are treated as a noisy but necessary way of detecting rare but
serious side effects of drugs that have not been detected in clinical
trials or animal studies.
8.10 The politics of therapeutic cannabinoid use
A puzzle in the field of cannabinoid therapeutics is that despite the
positive appraisal of the therapeutic potential of cannabinoids as
anti-emetics and anti-glaucoma agents, they have not been widely used.
Nor has the detailed type of clinical pharmacological research been
undertaken on optimal methods of clinical use in those areas where the
cannabinoids do have therapeutic potential (e.g. as anti-emetics).
Part of the reason for this is that research on the therapeutic use of
these compounds has become a casualty of the debate in the United
States about the legal status of cannabis. This emerges from an
inspection of the arguments recently advanced for and against an
application to the United States Drug Enforcement Agency to change the
status of marijuana under the Controlled Substances Act, 1970 from a
schedule I drug which has no accepted medical use to a schedule II
drug which has an accepted medical use (see Randall, 1988, 1989,
1990).
The proponents of rescheduling (National Organisation for the Reform
of Marijuana Laws, Alliance for Cannabis Therapeutics, and Cannabis
Corporation of America) have argued that marijuana should be available
for medical use, as smoking is the most effective mode of delivering
THC for some therapeutic purposes. The opponents of rescheduling (Drug
Enforcement Agency, International Chiefs of Police, The National
Federation of Parents for a Drug Free Youth) have countered that
marijuana has no therapeutic use, since its few uses are better met,
either by other more effective drugs which do not have the
psychoactive effects of THC, or by the oral delivery of synthetic
cannabinoids. They have been supported by medical researchers and
practitioners who argue for the therapeutic superiority of
pharmaceutically pure drugs which can be given in defined doses (e.g.
Levitt, 1986; Mechoulam, 1988; Nahas, 1984).
Medical researchers who have supported the rescheduling of marijuana
(e.g. Grinspoon and Bakalar, 1993; Merritt, 1988; Mikuriya, 1990;
Morgan, 1990; Weil, 1988) have argued that smoked cannabis is superior
to oral synthetic cannabinoids in effectiveness and has a lower risk
of producing unwanted psychoactive side-effects. Apart from the
unsuitability of oral medication for patients who are vomiting, their
main arguments in favour of smoking as a route of THC administration
are similar to the reasons recreational users often give for
preferring smoking to the oral use of cannabis. The greater
bioavailability of THC via smoking produces a more dependable
therapeutic effect, which is more easily controlled because users have
a greater ability to titrate their dose, and hence, to maximise the
desired effects while minimising the unpleasant effects. An additional
argument sometimes used is that there may be other cannabinoids
present in the crude plant product which modulate the undesired side
effects, including the unpleasant dysphoric effects of THC (Grinspoon
and Bakalar, 1993). There is also suggestive evidence that smoked
cannabis is as effective as oral THC, and may be preferred by patients
because of the greater control they have over dose (Chang et al,
1979).
Opponents of marijuana rescheduling argue that the undesirable
psychoactive side effects of THC disqualify it from widespread medical
use, whatever the route of administration. Most also believe that
smoking is a medically unacceptable route of administration of THC
because it is unsuitable for very young and very old patients, there
is a risk of infection with micro-organisms which may contaminate the
plant material, and there is the danger that chronic smoke inhalation
may produce or exacerbate bronchitis, and expose the user to
carcinogens (e.g. Levitt, 1986; Mechoulam, 1988; Nahas, 1984).
The proponents of rescheduling respond that none of these are
compelling reasons for rejecting smoked marijuana for therapeutic
purposes until more potent and specific therapeutic cannabinoids have
been identified and synthesised. Smoking, they point out, would not be
a compulsory method of administration; only an option for those
patients who preferred it, as would the use of cannabinoids if
patients did not like their psychoactive effects. The contamination of
micro-organisms reported with blackmarket cannabis can be overcome,
they argue, by standardising dose and using an anti-microbial
treatment, as has been done by National Institute on Drug Abuse (NIDA)
in preparing cannabis cigarettes for research (Randall, 1988). The
risks of bronchitis and respiratory tract cancers, it is argued, are
small with the intermittent and time-limited smoking of cannabis that
would occur in the course of cancer chemotherapy. In any case,
proponents of rescheduling argue, it is probably a risk that many
patients with a life-threatening illness may be prepared to run, as
shown by their preparedness to take highly toxic and carcinogenic
anti-cancer agents.
Weil (1988) has argued that some opponents have used double standards
in appraising the risks of marijuana smoking. According to Weil, the
most common psychoactive effects of marijuana (euphoria, somnolence
and dysphoria) are minor, non-life-threatening and self-limiting
effects that can be easily managed, and are of much less severity than
the side effects of many other widely-used therapeutic drugs. Medical
witnesses for the government, he claims, "do not contrast marijuana's
supposed adverse effects with the known adverse effects of drugs
routinely prescribed for the treatment of conditions like cancer,
glaucoma and multiple sclerosis. Instead, ... [they] compare marijuana
to some abstract, unobtainable standard of perfection" (p437).
Merritt (1988) has made a similar point in criticising the arguments
raised against the therapeutic use of marijuana to manage glaucoma: "
... each drug family used in glaucoma therapy is capable of producing
a lethal response, even when properly prescribed and used .. [p470]
[but] these drugs are all deemed "safe" for use in glaucoma therapy ..
because their adverse consequences are considered less threatening to
the patient than blindness" (p472). Yet marijuana is excluded from
therapeutic use because of a possible risk of cancer from long-term
daily smoking. "I cannot see", observes Merritt, "how an alleged case
of marijuana-induced lung cancer which results in death is
significantly different in result from an acute adverse reaction to a
myotic drug which results in respiratory failure, except, of course,
that the patient with cancer is likely to outlive the patient who is
unable to draw in a breath of air" (p474).
Although the debate about the rescheduling of marijuana has been
ostensibly about the safety and efficacy of marijuana use, it has been
driven by the debate about the legal status of recreational marijuana
use. For example, some of the groups advocating the therapeutic use of
cannabis have also been proponents of cannabis legalisation (e.g.
NORML), thereby fuelling the fears of opponents of cannabis use that
success in the campaign for marihuana rescheduling will be the thin
edge of a wedge to legalise cannabis. Other proponents of legalisation
(e.g. Grinspoon and Bakalar, 1993) have turned this reasoning around,
by arguing for the legalisation of cannabis as a way of making
cannabis available for therapeutic purposes.
On the other side of the argument are those opponents of marijuana use
who fear that the admission that marijuana, or any of its
constituents, may have a therapeutic use will send the "wrong message"
to youth. This has led to the denial that cannabinoids have any
therapeutic effects, and to attempts to stifle all scientific inquiry
into any such effects. For example, Mr Bernstein representing the
National Federation of Parents for a Drug Free Youth had the following
to say in his summing up against Rescheduling marijuana before Judge
Young (1989):
"If marijuana were to be rescheduled to Schedule II, what kind of
message are we sending to a nation that is engaged in a battle for
it's very survival because of epidemic drug abuse? ... will not the
message be that marijuana is good for cancer, good for glaucoma, good
for spasticity and a host of other illnesses? Now to all of this who
are the most vulnerable? The answer is, of course, our young people.
Their reaction will be that if it is good for all of these things, it
can't be bad for me. We then have another youngster trying marijuana,
the gateway drug and probably starting down the road that leads to
nowhere but destruction" (in Randall, 1989, p395).
It is unfortunate that a connection has been forged between the
debates about the legal status of cannabis as a recreational drug and
the use of cannabinoids for therapeutic use. Any such connection is
spurious, since there is a world of difference between the use of
controlled doses of a purified drug under medical supervision and the
recreational use of crude preparations of a drug. In a rational world,
clinical decisions about whether to use pure cannabinoid drugs should
not be abrogated because crude forms of the drug may be abused by
those who use it recreationally. As a community we do not allow this
type of thinking to deny us the use of opiates for analgesia. Nor
should it be used to deny access to any therapeutic uses of
cannabinoids derivatives that may be revealed by pharmacological
research.
8.11 Conclusions
The following provisional conclusions can be drawn on the available
evidence. First, there is good evidence for the therapeutic potential
of THC as an anti-emetic agent. Although uncertainty exists about the
most optimal method of dosing and the advantages and disadvantages of
different routes of administration, there is sufficient evidence to
justify it being made available in pure synthetic form to cancer
patients. In the light of the recent development of more effective
anti-emetic agents, it remains to be seen how widely used the
cannabinoids will be. Second, there is reasonable evidence for the
potential efficacy of THC in the treatment of glaucoma, especially in
cases which have proved resistant to existing anti-glaucoma agents.
Further research is clearly required, but this should not prevent its
use under medical supervision in poorly controlled cases, provided
patients make informed decisions about its use in the light of
information about the possible health risks of long-term use. Third,
there is sufficient suggestive evidence of the potential usefulness of
various cannabinoids as analgesic, anti-asthmatic, anti-spasmodic, and
anti-convulsant agents to warrant further basic pharmacological and
experimental investigation, and perhaps clinical research into their
effectiveness.
Despite the basic and clinical research work which was undertaken in
late 1970s and early 1980s, the cannabinoids have not been widely used
therapeutically, nor have further investigations been conducted along
the lines suggested in the positive evaluations made by the Institute
of Medicine (1982). This seems largely attributable to the fact that
clinical research on the therapeutic use of cannabinoids has been
discouraged by regulation and a lack of funding in the United States,
where most cannabis research has been conducted. The discouragement of
therapeutic research, in turn, derives from the fact that THC, the
most therapeutically effective cannabinoid, has the psychoactive
effects sought by recreational users. In opposing the therapeutic uses
of cannabinoids, some researchers have used double standards in
appraising efficacy and safety, setting unreasonably high standards in
assessing the evidence on the comparative therapeutic safety and
efficacy of cannabinoids and existing agents. The application of the
same demanding standards to existing agents for the candidate
diseases, and more generally, to existing psychoactive drugs that are
widely used in medical practice, would denude the pharmacopoeia. The
recent discovery of the cannabinoid receptor may help to overcome some
of the resistance to research into the therapeutic uses of
cannabinoids, by holding out the prospect that the psychoactive
effects of the cannabinoids can be disengaged from their other
therapeutically desirable effects.
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