Reprinted from:
MEDICINAL
USE OF CANNABIS: HISTORY AND CURRENT STATUS
Harold
Kalant, M.D., Ph.D.
Professor
Emeritus
Department
of Pharmacology, University of Toronto
and
Centre for Addiction and Mental Health,
Ontario
Running title: Medical use
of cannabis and cannabinoids
Address for correspondence:
Dr. H. Kalant
Department of Pharmacology
Medical Sciences Building
University of Toronto
Toronto, Ontario M5S 1A8
tel: (416) 978-2730
fax: (416) 978-6395
e-mail: harold.kalant@utoronto.ca
ABSTRACT
OBJECTIVE: To provide an
overview of the history and pharmacology of cannabis in relation to present
scientific knowledge concerning actual and potential therapeutic uses of
cannabis preparations and pure cannabinoids.
METHODS: The literature on
therapeutic uses of cannabis and cannabinoids was assessed with respect to type
of study design, quality and
variability of data, independent replications by the same or other
investigators, magnitude of effects, comparison with other available
treatments, and reported adverse effects. The results of this review were also
compared with those of major international reviews of this topic in the past
five years.
CONCLUSIONS: Pure THC and several analogs have shown
significant therapeutic benefits in the relief of nausea and vomiting, and
stimulation of appetite in patients with wasting syndrome. Recent evidence
clearly demonstrates analgesic and antispasticity effects that will probably
prove to be clinically useful. Reduction of intraocular pressure in glaucoma,
and bronchodilatation in asthma, are not sufficiently strong, long-lasting, and
reliable to provide a valid basis for therapeutic use. The anticonvulsant
effect of cannabidiol is sufficiently promising to warrant further properly
designed clinical trials. There is still a major lack of long-term
pharmacokinetic data, and information on drug interactions.
For all the present and
probable future uses, pure cannabinoids, administered orally, rectally, or
parenterally, have been shown to be effective, and they are free of the risk of
chronic inflammatory disease of the airways, and upper repiratory cancer, that
is associated with the smoking of crude cannabis. Smoking might be justified on
compassionate grounds in terminally ill patients who are already accustomed to
using cannabis in this manner. Future research will probably yield new
synthetic analogs with better separation of therapeutic effects from undesired
psychoactivity and other side effects, and with solubility properties that may
permit topical administration in the eye, or aerosol inhalation for rapid
systemic effect without the risks associated with smoke inhalation.
Key Words: Cannabis; Cannabinoids; History;
Therapeutic use; Routes of administration; Adverse effects.
Despite the recent surge of
interest in the potential
medical use of cannabis, it is worth remembering that cannabis is not a new
drug. It has a very long history of medical as well as non-medical use in many
parts of the world. In discussing possible clinical trials of cannabis or
cannabinoids, there is something useful to be learned from recalling a little
of that history.
Historical background
The cannabis or hemp plant
has been known since antiquity, and grows in almost all parts of the world, but
has been known principally as a source of useful fibre for the manufacture of
textiles and rope1. In most fibre-producing areas the plant was not
used as a drug. Geographic and climatic factors modify the content of
pharmacologically active material in the plant, and only in some regions was
this content high enough to lead to the discovery that the plant, and
especially its resin, had important drug actions. Knowledge of these actions
appears to have arisen first in the Himalayan region of central Asia, and spread gradually from there to
India, Asia Minor, North Africa, and across the desert to sub-Saharan Africa and the rest of the African
continent2-4.
In India, the plant was used both medically
and non-medically5. Its social and religious uses were related most
notably to the festival of Durga Puja. On a few other occasions during the year
it was also used in family celebrations such as marriages and births, to induce
a relaxed and sociable mood and a good appetite. Only the weaker preparations
were used: bhang (comparable to marijuana) was taken by mouth, and the
slightly stronger preparation ganja was smoked, but the most potent
preparation, charas (known elsewhere as hashish) was not used for these
purposes. Indeed, use of charas was not socially approved for any purpose, and
its devotees were regarded as "bad characters" or outcasts.
Cannabis also formed part
of the therapeutic armamentarium of traditional Indian medicine, and many of
the uses to which it was put were similar to those for which it is advocated in
our own society today. Among its claimed benefits were: sedative, relaxant,
anxiolytic and anticonvulsant actions, all of which also made it useful in the
treatment of alcohol and opiate withdrawal; analgesia; appetite stimulation;
antipyretic and antibacterial effects; and relief of diarrhoea6.
The introduction of the
drug effects of cannabis into Europe in the 19th century followed different routes for the
medical and non-medical uses. In France, interest centred on the
non-medical application of the psychoactive effects, whereas in England the interest was primarily medical.
During the Napoleonic invasion of Egypt in 1798, De Sacy and Rouyer, two
French scholars who accompanied the army, described the plant and the practice
and effects of hashish smoking, and they collected samples of the material to
take back to France for further study4. The
famous French psychiatrist, Moreau de Tours, made further observations of its
effects on mood during his North African travels in the 1830s. He later
described in detail the mental effects of high doses of hashish, and advanced
the hypothesis that dreams, insanity, and drug intoxication involve similar
mechanisms. He proposed the use of hashish to produce a "model
psychosis" for scientific study7,8, a full century before this
concept was proposed in North America in connection with the hallucinogens LSD and
mescaline. In Paris, the "Club des Haschichins" flourished in
the 1850s, with such members as the poets and authors Baudelaire, Gautier and
Dumas. They served as subjects for Moreau's experiments, and popularized
hashish in their writings, as a claimed route to aesthetic self-realization, as
Ginsberg and others did in the United States over a century later.
In the United Kingdom, on the other hand, interest in
cannabis was aroused by the medical and scientific writings of O'Shaughnessy9,
a British physician working in India as Professor of Chemistry and
Materia Medica in Calcutta. He observed the use of cannabis in
Indian traditional medicine, for the treatment of spastic and convulsive
disorders such as "hydrophobia" (rabies), tetanus, cholera, and
delirium tremens. He sent supplies of the material to a pharmaceutical firm in London for analysis and clinical trials.
The extracts of cannabis were adopted into the British Pharmacopoeia and later
into the US Pharmacopeia, and were widely used in the English-speaking world as
sedative, hypnotic and anticonvulsant agents in the late 19th and early 20th
centuries10,11.
Yet, by the time that
cannabis was dropped from the British Pharmacopoeia in 1932 and the US
Pharmacopeia in 194112, its clinical use had virtually disappeared
and its formal banishment evoked little or no protest. Among the reasons for
this loss of favor were that the plant material was too variable in
composition, its shelf-life was too short and unpredictable13, and
it had been increasingly replaced by pure opiates and more reliable new
synthetic drugs invented in the early part of the 20th century2,11.
Therefore cannabis would have to be substantially improved as a drug if it was
to regain clinical interest.
Early and modern
chemical studies
The very high lipid
solubility of the materials responsible for the drug effects of cannabis was
known in North
Africa,
where a common practice was to heat the leaves and flowering tops of the plant
in a mixture of butter and water10. The active drug materials
concentrated in the butter phase and, as the mixture cooled, the butter could
be separated from the water and used in preparations to be taken by mouth to
produce the desired effects. In 1857, the Smith Brothers of Edinburgh prepared
a non-alkaloidal fraction with a high level of drug activity, and alcoholics
extracts or the dry residues obtained from them were later standardized for
their biological activity, forming the basis of the pharmacopoeial
preparations. In 1899, Wood, Spivey and Easterfield attempted to isolate the
active agents from such preparations, but their "cannabinol" had very
little pharmacological activity and proved to be a mixture rather than a single
compound (cited by Todd14).
It was not until the 1930s
and 1940s that Todd et al.15 in the UK and Adams et al16 in the USA isolated pure cannabidiol and
various tetrahydrocannabinols, and showed that the latter were responsible for
the psychoactive effects. The relationship of crude cannabis preparations
(marijuana and hashish) to pure cannabinoids is shown schematically in Figure
1. Of the numerous chemical compounds isolated from cannabis, only three have
the typical psychoactive effects for which cannabis is used non-medically: ?9-tetrahydrocannabinol
(?9-THC), ?8-tetrahydrocannabinol (?8-THC) and (very weakly) cannabinol17,18.
A fourth natural cannabinoid, cannabidiol, has other types of pharmacological
activity but is not psychoactive.
Finally, Mechoulam et al19
in Israel, and Claussen and Korte20
in Germany, achieved the complete synthesis of
the pure compounds, established their molecular structures, and began the study
of their structure-activity relationships. This work led to the synthesis of
new cannabinoid derivatives and analogues that do not exist in nature. Armed
with these pure and potent chemicals, Devane et al.21 identified
specific binding sites (cannabinoid receptors) in the brain, and showed that
the receptor-binding affinities of the different compounds paralleled their
respective potencies of biological activity. Since cannabinoids themselves do
not exist in the brain, the existence of the receptors implied that some other
endogenous material in the brain normally binds to them. Devane et al.22
later reported the isolation of anandamide (arachidonyl-ethanolamine), a lipid
material related to the prostaglandins, that is formed locally in the brain and
binds to the receptors, exerting actions similar to those of the cannabinoids
but less potent. Arachidonyl-glycerol and several other such materials have
been identified subsequently.
The cannabinoid receptors
were found to be of at least two different types3,23, the CB1
receptors present mainly in various parts of the brain (cerebral cortex, cerebellum,
basal ganglia, limbic system, hypothalamus, hippocampus), and the CB2
receptors present exclusively in peripheral tissues such as the immune system,
bone marrow, lung, pancreas and smooth muscle. Both receptor types are linked
to the inhibitory G protein, through which they act to inhibit adenylyl cyclase
activity, preventing the activation of various Ca2+ channels in the
cell membrane, while increasing K+ influx3,23. The
functional results vary in different types of neuron. Inhibitory neurons are
activated, with increased GABA release24, while in motor neurons
cell excitability and neurotransmitter release are decreased. The isolation of
the different types of receptor has made it possible to develop wholly
synthetic compounds with high selective affinity for one or other type, some
acting as agonists and others as antagonists18. The availability of
these receptor-specific ligands has permitted rapid advances in analyzing the
cellular mechanisms underlying various pharmacological effects of the cannabinoids.
The structures of some of the main natural and synthetic cannabinoids are shown
in Figure 2, and their relative affinities for CB1 and CB2
receptors in Table 1.
Pharmacokinetics
Cannabinoids can be
administered by a variety of routes. Because of their high lipid solubility, topical
administration is possible in such locations as the eye or the nasal mucosa.
However, this has been of very limited applicability, because preparations of THC available in the past tended to be
irritating 25 to the eye. However, newer vehicles that permit
lipid-soluble materials to be applied to the eye in aqueous solution may make
this route of greater interest again 26. In theory, percutaneous
absorption, as from a drug-impregnated skin patch, should be possible, but the
absorption would be very slow and not clinically useful.
Oral administration results in a slow
and variable absorption, with a bioavailability of 10-20%, and usually less
than 15% 3,27-29. There is also a high hepatic uptake from the
portal venous blood, and an active first-pass metabolism in the liver.
Nevertheless, this does not result in a loss of pharmacological activity,
because the major first-pass metabolite, 11-hydroxy-THC, is at least as potent a
psychoactive agent as THC itself3. THC can also be converted to a
hemisuccinate and administered as a rectal suppository30.
Absorption is quite good by this route, with much higher bioavailability than
after oral administration. In addition, rectal absorption delivers the drug
directly into the systemic circulation, thus avoiding the first-pass
metabolism.
Intravenous injection or
infusion is
possible, but because of the very low water-solubility of cannabinoids a
special formulation must be used, such as a complex of the cannabinoid with
plasma protein, or a solution in a water-miscible organic solvent. Without such
formulations, almost no active material can be delivered, and intravenous
toxicity is due essentially to injection of insoluble particulate material31.
Intravenous administration of suitable preparations gives a very rapid onset of
action, but because of dosage limitations to avoid excessive intensity of the
peak effect, the duration of action is short.
Smoking is undoubtedly the best-known
method of administration, and is the typical manner of using crude marijuana,
as opposed to pure cannabinoids. Much of the total THC in crude cannabis is not free THC but tetrahydrocannabinolic acid32.
The heat just ahead of the advancing zone of combustion in a cigarette or
pipeful of cannabis converts the THC acid to free THC33, and volatilizes the THC so that it can be inhaled with the
smoke, deep into the lung. The high lipid-solubility of the THC allows it to cross the alveolar
membrane rapidly, entering the blood in the pulmonary capillaries. From here it
is carried rapidly to the heart and pumped directly to the brain, so that the
onset of action is at least as rapid as with intravenous injection. The
bioavailability of THC by this route ranges from 18 to 50% in different studies.
Much of the variation is due to individual differences in smoking technique,
relating to volume of the "draw", depth of inhalation into the lungs,
and duration of retention of the smoke in the alveoli34,35. Both the
peak plasma THC level and the intensity of subjective effects are directly proportional
to the puff volume and frequency34. The time course of action of
smoked cannabis is very similar to that of intravenous THC, with rapid onset, high peak
intensity, and short duration.
Like other highly
lipid-soluble drugs, THC in the plasma is largely transported as a loosely bound
complex with plasma protein. This complex dissociates readily, so that the free
THC rapidly crosses cell membranes and
enters the tissues in proportion to their respective blood flow rates. Not surprisingly,
therefore, the time course of THC concentrations in the different tissues are very
much like those of thiopental36,37. The plasma THC concentration curve after cannabis
smoking is therefore triphasic: a rapid absorption phase with a t2 of 50 sec, a
slower tissue distribution phase with a t2 of 40-80 min, and a much slower
metabolic elimination phase with a half-life that varies considerably in
different studies3,28, but is most typically about 2-3 days. A
variety of metabolites appear in the urine and feces, but the major one in
urine is 11-nor-9-carboxytetrahydrocannabinol. The 72-hour cumulative excretion
of total metabolites, expressed as a percentage of the administered dose,
amounts to 13-17% in the urine and 25-30% in the feces after IV injection or
smoking, but the fecal excretion increases to 48-53% after oral ingestion27.
Chronic use appears to
produce little or no increase in the rate of metabolism (i.e., no appreciable
shortening of the t2 of the third phase)38, so that there is a
potential risk of cumulative increase in the tissue concentrations over time,
in daily users.
Pharmacological effects
(a) Acute effects
Both crude cannabis and
pure THC have a wide range of
pharmacological effects, only some of which are of potential therapeutic
interest.
Central nervous system - Cannabis acts essentially as a CNS depressant3,39,40, so
that its main acute effects in many ways resemble those of alcohol. It produces
drowsiness and decreased alertness, being synergistic with alcohol, barbiturates
and other CNS depressants in this respect2,41,42. Similarly, though THC has minimal respiratory depressant
effect by itself, it may be synergistic with other depressants. Cognitive
effects include impairment of short-term memory, slowed reactions, decreased
accuracy of psychomotor task performance, and decreased selectivity of
attention (greater interference by extraneous stimuli). Motor coordination and
muscle tone are also decreased, resulting in ataxia43,44. As a
result of all of these effects, it causes poorer performance in simulated
driving45 or flying46 tasks. However, the risk for
real-life driving may be less than with equivalent levels of alcohol
intoxication because the cannabis users appear to be more cautious and less
aggressive45.
Low doses of cannabis
typically induce mild euphoria, relaxation, increased sociability, and
decreased anxiety. However, high doses often result in dysphoria, increased
anxiety, and panic reactions, especially in inexperienced users. Similarly, low
doses tend to increase sensory acuity, often in a pleasurable way, whereas high
doses may cause sensory distortion, hallucinations, and even an acute toxic
psychosis that is usually of short duration after the drug is discontinued47.
Pain perception is
diminished, and pain tolerance increased, by a central action of THC that is separate from that of
opioid analgesics48-51. It is exerted at CB1 receptors in
the central grey matter, and local injection of THC or its synthetic analogs at this
site is effective in alleviating pain52. However, there also appear
to be spinal cord sites53 and peripheral sites54 that
contribute to the analgesic action. The CB1 receptor blocker SR
141716A prevents the analgesic effect of THC but not of morphine55,
whereas naloxone blocks the morphine analgesia but not that produced by THC or its analogs23.
Antinauseant and antiemetic
effects of THC, nabilone and other cannabinoids have been well demonstrated56.
These effects appear to be due mainly to action in the CNS, though they may be partly of peripheral
origin also. There is also a well-demonstrated increase in appetite, that
results in increased food intake57-59, though this is preferential
for sweet foods, i.e., carbohydrate rather than protein, and much of the
observed weight gain appears to be fluid retention.
All of the foregoing
effects are produced by cannabinoid actions on the CB1 receptors.
In contrast, an
anticonvulsant effect of THC60-61 does not appear to be produced via CB1
receptors, because cannabidiol (which does not bind to the CB1
receptor) is at least as effective as THC in preventing or suppressing
seizures62-64. Both drugs have electrophysiological effects similar
to those of phenytoin in experimental animal models of epilepsy.
Neuromuscular system - Apart from the centrally mediated
effect on skeletal muscle tone, there appears to be a more peripherally
mediated antispasticity action. It is not clear whether this is exerted in the
spinal cord or at peripheral sites such as the nerve-muscle junction65.
Cardiovascular effects - One of the most consistent and
reliable signs of acute action of cannabis is tachycardia, with increased
cardiac output and correspondingly increased myocardial oxygen requirement.
These effects are generally mild, and of no pathological significance, but the
increased myocardial workload could in theory become dangerous in an individual
with some degree of coronary insufficiency66. The tachycardia may
possibly be a compensatory reaction to cannabis-induced vasodilatation, that is
often revealed as orthostatic hypotension.
Respiratory system - One of the manifestations of
smooth muscle relaxation by cannabis or THC is bronchodilatation, with
resulting decrease in airway resistance. This is an acute effect, but with
chronic use it tends to be offset by bronchial irritation caused by the
particulate fraction of cannabis smoke67. Since cannabis smoke is
similar in most respects (other than cannabinoid content) to tobacco smoke, the
consequences of chronic exposure to cannabis smoke are similar to those of
tobacco smoke67.
Eye - Cannabis and THC have been shown repeatedly to lower
the intraocular pressure, by a mechanism that is not yet understood26.
This effect can be produced by systemic administration at doses that also
produce the characteristic CNS effects, and rather inconsistently by local application to
the eye.
Immune system - In vitro exposure to very high
concentrations of THC results in decreased function of macrophages, lymphocytes
and NK cells68. In vivo, however, the observations are highly
variable in different studies, and it is not yet clear whether there is or is
not a significant effect of cannabis smoking on immune functions. Experimental
studies in mice have suggested that resistance to Legionella infection may be
decreased by THC68. The risk of pulmonary aspergillosis is increased in AIDS patients68-71,
but it is difficult to know whether cannabis is acting as an immunosuppressant
or simply as the source of the fungal contaminant72. In any case,
the in vitro effects on immune cells are probably not produced via CB1
receptors, because they are also produced by cannabinoids that lack the
psychoactivity of THC.
(b) Chronic effects
In contrast to the
potential therapeutic interest in the acute effects described above, changes in
these effects that may occur with chronic use are linked mainly to the
production of adverse effcts that may limit the therapeutic usefulness of
cannabinoids.
Central nervous system - Prolonged daily use of cannabis
has been linked to a variety of cognitive changes, including poor memory,
vagueness of thought, decreased verbal fluency, and learning deficits, that are
not always fully reversible when use of the drug is stopped47.
High-dose daily use can give rise to a chronic intoxication syndrome,
characterized by apathy, confusion, depression and paranoia. Cannabis
dependence, that meets the DSM-III-R criteria, has now been well documented in regular
heavy users73-75. Among the components of this dependence are
increased tolerance to most of the effects of cannabis, and physical dependence
in the form of a relatively mild spontaneous withdrawal syndrome or a more
severe one precipitated by the CB1 antagonist SR 141716A3,75-79.
This precipitated withdrawal is analogous to the reaction provoked by naloxone
in a dependent opiate user. Cannabis use has also been reported to precipitate
clinical relapse in compensated schizophrenics, producing a picture that
differs from that of spontaneous relapse in which cannabis use may be merely a
symptom43,80-82. Finally, the offspring of women who smoke cannabis
during pregnancy have been reported to show subtle but apparently permanent
cognitive and personality changes (impulsiveness, poor memory, decreased verbal
fluency and verbal learning) when they reach school age83,84.
Respiratory system - Two relatively large-scale
studies of pulmonary function in chronic cannabis and tobacco smokers have
given contradictory findings with respect to chronic obstructive pulmonary
disease (COPD). One study, using a "convenience sample" (i.e.,
recruited through advertisements) of young chronic smokers of tobacco,
marijuana, or both, as well as non-smokers, found a clear linkage of COPD to
tobacco smoking, but not to marijuana smoking75. In contrast, a
larger study using a systematic population sample subjected to very similar
pulmonary function tests, found a significant link between COPD and marijuana
smoking, as well as an additive effect of tobacco and marijuana86.
The reason for the difference between the findings of the two studies is not
yet entirely clear, but the two agreed that chronic inflammatory changes were
definitely increased in cannabis smokers.
Chronic inflammatory chest
disease has been reported to be present in over 60% of long-term daily smokers
of cannabis, in some studies67,73,74,87. Precancerous changes in
bronchial epithelial cells have been described in such users, and there are a
number of case reports of upper airways malignancy or premalignant changes in
young smokers of cannabis (aged less than 30 years, i.e., much younger than is
typical of tobacco-induced bronchial carcinoma)67,87-90. Although
one prospective study of a large clinic population found no apparent increase
in risk of lung cancer in cannabis users compared to the non-users91,
this study is flawed by its inclusion, in the group of cannabis users, of
individuals who had used it as little as six times in their life. A much better
designed recent case-control study of patients with proven upper airways cancer
indicated a significant increase in risk among cannabis smokers, even after
correction for concurrent tobacco use, and the increase in risk was
proportional to the frequency and duration of cannabis use92. The
authors of the latter study systematically considered possible sources of
error, such as selection bias, misclassification of cannabis exposure, low
power and precision, etc., but were able to discard these by appropriate
statistical comparisons of the control group with the general population. They
recognized the need for larger-scale comparisons as more long-term cannabis
smokers become available for study, but their findings point to a significant
risk. This is consistent with the experimental demonstration of mutagenicity of
cannabis smoke in the Ames test, which is probably not an effect of THC but of the particulate fraction of
the smoke87.
Other systems - Heavy smokers of cannabis have
shown various endocrine changes, including decreased testosterone levels and
reduced sperm counts in males, and decreased LH and prolactin levels in the
luteal phase of the menstrual cycle in females, resulting in shorter periods
and more anovulatory cycles. However, the clinical importance of these changes
is uncertain, since tolerance may develop to these effects of cannabis.
Decreased levels of thyroxine and of corticosteroids have been found in
experimental animals receiving high doses of cannabinoids, but such changes
have not been clearly demonstrated in humans93. Similarly, high
doses of THC have been found to impair protein and nucleic acid synthesis in rats,
but the significance of these findings for humans remains unclear. Tolerance
also develops to the acute cardiovascular effects of cannabis, and chronic use
has not been shown to cause any significant harm to the cardiovascular system.
Medical uses of
marijuana and cannabinoids
The history of drug therapy
has been to a large extent one of progressive movement away from natural
products of unknown or variable composition and potency, toward the use of pure
active compounds of precisely known composition, stability, dosage and
pharmacology. In light of the reasons why cannabis fell out of favour as a
medication nearly a century ago, and the great advances in chemistry and
pharmacology of cannabinoids in recent years, the current revival of interest in
clinical trials of smoked marijuana for therapeutic purposes may seem like a
backward step. Does it have any valid scientific basis? The following section
explores what arguments can be raised for and against it.
Of the acute effects of
cannabis and cannabinoids described above, the following appear to offer
possible therapeutic applicability:
$ low-dose euphoriant and
anxiolytic effects, as possible treatment for depression and anxiety
$ anticonvulsant action, as
an adjuvant therapy for epilepsy
$ analgesia
$ antinauseant and
antiemetic action, in treatment of patients receiving radiation therapy or
chemotherapy for AIDS or cancer
$ appetite stimulation in
patients with anorexia and wasting syndromes
$ reduction of intraocular
pressure in the treatment of glaucoma
$ bronchodilatation in the
treatment of asthma
$ immunosuppressant action
in the treatment of autoimmune diseases or to prevent rejection of transplanted
organs or tissues.
Of these possibilities, the
antinauseant, antiemetic and appetite stimulating effects have already been
reviewed in detail elsewhere12 and approved as indications for the
therapeutic use of pure THC in patients with AIDS or cancer. The potential
antidepressant and anxiolytic actions so far have not been supported by
sufficient experimental evidence, in either laboratory animals or humans, to
warrant the effort and expense of full-scale clinical trials. As mentioned
earlier, the bronchodilatory effect does not appear to be sufficiently
long-lasting to be of potential interest in the treatment of asthma, and there
is insufficient evidence at present to justify clinical trials of the
immunosuppressant action in autoimmune disease or transplant rejection. At
present, therefore, the most interesting possibilities for clinical exploration
are probably analgesia, relief of muscle spasm, reduction of intraocular
pressure, and anticonvulsant action.
In most potential
therapeutic applications, the psychoactive effects - i.e., the "high"
- constitute an undesirable side-effect, interfering with the patient's ability
to carry out a variety of normal psychomotor functions. It then becomes
important to see whether the desired therapeutic effects can be separated from
the undesired psychoactive effects at appropriate doses, and to select the most
appropriate routes of administration to achieve this goal. The current status
of the relevant research is considered below in relation to the four major
potential uses identified above.
Analgesia
Although earlier studies
failed to confirm a consistently useful degree of analgesia with either
intravenous THC, oral cannabinoids, or smoked cannabis49, short-term trials
in humans have demonstrated the ability of oral or parenteral THC, levonantrodol and cannabis extract
to decrease post-operative94, dental95, cancer96
and visceral97 pain. The latter was a double-blind
placebo-controlled cross-over subacute study in a single patient with chronic
gastrointestinal pain due to familial Mediterranean fever. A marked reduction
of pain was achieved with oral administration of a cannabis extract at a dose
providing 50 mg of THC daily97. However, there is still a need for
controlled studies of its efficacy in chronic pain such as musculoskeletal,
arthritic, and cancer-induced pain. A recent animal study has indicated the
efficacy of a synthetic cannabinoid in an experimental model of neurogenic pain98,
but there is only sparse anecdotal evidence for its ability to relieve migraine99.
Nevertheless, the modern neuropharmacological studies cited earlier leave no
doubt that there is an analgesic action at appropriate doses. Since the
mechanisms of opioid-induced and cannabinoid-induced analgesia differ, there is
interest in the possibility that a combination of the two drugs, at lower doses
than would be used for either alone, might result in improved analgesia with
lower risk of the typical side effects of each drug50.
In open-label, uncontrolled
studies, both smoked cannabis and oral cannabinoids have been reported to be
effective analgesics100. The onset of action is more rapid with
smoking, but there are few situations in which this is an important
consideration. In chronic pain, for example, the therapeutic objective is to
maintain consistent and continuous analgesia, so that successive doses are
timed to have overlapping effects, and the difference in speed of effect would
apply only to the first dose. Indeed, the less intense and more prolonged
effect of oral THC would appear to offer an advantage over the more intense
but shorter-lasting effect of smoked cannabis. Moreover, for long-term use in
chronic painful disorders, such as musculoskeletal problems, the pulmonary
complications of smoking would be a distinct disadvantage.
Some of the new synthetic
derivatives or analogs of THC may offer improved possibilities for therapeutic use.
Water-soluble esters of the THC acids appear to have both analgesic and
anti-inflammatory action, without the undesired psychoactive effects of THC itself. Since they do not produce
gastric irritation, they might be useful substitutes for the current
non-steroidal anti-inflammatory agents101,102.
Relief of muscle
spasticity
Numerous claims have been
made for the ability of cannabis to relieve muscle spasms, especially in
multiple sclerosis, but most of these claims consist of unverified subjective
reports, rather than controlled studies. A case report of one patient described
the suppression of pendular nystagmus by the smoking of cannabis103.
A self-report study, based on interviews with 112 multiple sclerosis patients
in the United Kingdom and the United States who smoked marijuana, found that
the main benefits claimed by the users were decreased spasticity and pain, but
other claimed benefits included decreased bladder spasm and improved balance
and walking104. However, the known pharmacology of cannabis makes it
difficult to see how this drug could improve balance. Indeed, an experimental
study of 10 multiple sclerosis patients and 10 healthy controls, each smoking
one marijuana cigarette, found that marijuana caused worse posture and balance
in both groups, but more so in the patients than in the controls105.
Nevertheless, several controlled studies with objective measures of spasticity
as well as subjective self-reports have shown improvement after oral and rectal
administration of THC or nabilone106-109. To date, there have been no
controlled studies comparing the antispasticity effects of smoked marijuana and
oral THC in the same patients, and no
controlled comparisons with other drugs currently used for the relief of spasm.
Glaucoma
In about 65% of both normal
subjects and patients with glaucoma, THC has been shown to reduce the
intraocular pressure (IOP), and both oral THC and smoked cannabis are effective21.
After smoking marijuana, the fall in IOP reaches its peak in about 2 hr and is
gone by 3-4 hr. The therapeutic objective of preventing retinal and optic nerve
damage in glaucome requires a continuously sustained fall in IOP. To produce
such a sustained effect with marijuana, it would be necessary to smoke it 8-10
times a day26. The effect of oral THC is more prolonged, and fewer doses
a day would be required, but it is still not possible to avoid the psychoactive
effects at THC doses that would provide a useful reduction of IOP.
Potential future
developments will rest on synthetic analogs with a superior separation of
effects. For example, dexanabinol (CH211) lowers the IOP but appears to be
devoid of psychoactivity at ophthalmologically useful doses26. Other
synthetic analogs with higher water-solubility than THC itself are under development. Such
compounds might permit topical use as eye-drops, without need for the
irritating solvents used as vehicles for THC itself.
Anticonvulsant use
As noted earlier in this
review, numerous animal experiments have demonstrated that both THC and cannabidiol have phenytoin-like
effects in models of grand mal seizures, but tolerance develops rapidly to this
action of THC61. One well-designed, but unfortunately rather small-scale, double-blind
controlled study110 has been carried out in epileptics who did not
have adequate therapeutic benefit with conventional agents despite apparently
good compliance. When oral capsules of cannabidiol were added as a supplement
to their regular treatments, their seizure frequency was significantly less
than when they received supplementary placebo capsules. Two other double-blind
placebo-controlled clinical trials of cannabidiol in epileptics, carried out
since then, are said to have shown no therapeutic effect111,112,
but unfortunately these have not been published in detail. No comparison of the
efficacy of smoked marijuana versus oral cannabinoids has been reported. Since
cannabidiol is not psychoactive, and its oral use does not carry the pulmonary
risks of smoking cannabis, it seems worth while for cannabidiol to be made
available for more extensive clinical trials.
Problems in the design
of clinical trials of cannabis
Almost all of the data on
the pharmacokinetics of cannabinoids are derived from acute single-dose
studies, and very little is known about possible changes in pharmacokinetics
during long-term chronic use. The long elimination t2 of THC means that there is a potential
risk of accumulation of the drug in the body during chronic therapy, so that
there is a need to monitor residual levels regularly during chronic studies.
This problem is complicated by the very high lipid-solubility of THC, which means that the drug passes
very rapidly from the plasma to the tissues, where it accumulates. Thus, the
plasma level can not be used as a measure of the tissue levels for more than
the first few minutes after administration of THC113,114 and the degree of disparity will
differ with different routes of administration. The slower the rate of
absorption, the lower will be the plasma level relative to the tissue levels of
THC. For this reason, the usual methods
of estimating bioavailability may not be valid, especially for comparing
bioavailability by different routes.
Another potential problem
is that cannabidiol (CBD) is an effective inhibitor of cytochrome P450 activities
when given acutely115, and an inducer when given chronically116.
The same is true of the polycyclic hydrocarbons in cannabis smoke, as in
tobacco smoke. There is thus a significant risk of drug interactions, both
acutely and chronically, including a metabolic interaction between CBD and THC itself117. This
consideration applies to the use of smoked marijuana, but to a much smaller
degree to that of pure THC115. The variability of this effect with different
preparations, and with acute vs. chronic administration, may account for the
widely differing findings concerning interaction between THC and CBD. CBD has been found to enhance
the effects of THC in some studies117-119, to reduce or
abolish them in others120-125 and to produce no change in still
others126.127. This marked variability of interaction illustrates
one of the advantages of using single pure cannabinoids.
Many of the potential
therapeutic uses of cannabis would be chronic or lifelong. Therefore it is
necessary for clinical trials to be of long enough duration to assess the
quantitative impact of tolerance on the desired therapeutic effect.
Consideration must also be given to the risks of pulmonary damage from smoking
cannabis, and the risk of dependence on THC by any route.
As with any drug, clinical
trials of cannabis or cannabinoids must consider whether the potency and
selectivity of their pharmacological effects provide an acceptable risk:benefit
ratio for clinical use. Unfortunately, very few trials in the literature have
used more than 2 or at most three dose levels, and the effects that have been
measured have consisted principally of subjective "high", heart rate,
and one or two other convenient physiological or psychomotor functions. There
is thus a great need for thorough dose-response studies with respect to both
the proposed therapeutic uses and a broad range of potential adverse effects,
in order to define the safety factor or "margin of safety". As much
as possible, the measures should be objective and quantifiable, rather than
subjective or of the yes/no type. Some of the potential applications, such as
relief of pain or spasm, are clearly subject to the effects of suggestion and
expectancy, so that the design of the trial is extremely important for ruling
out the placebo effect or the influence of bias either for or against the use
of cannabis.
For some of the possible
applications, the numbers of available subjects may be too small to permit
useful trials at single locations, so that multicentre studies may be required.
Finally, for some of the potential therapeutic applications, cannabis or
cannabinoids are less potent and less effective than some of the existing
therapies, and would therefore be added to these rather than replace them.
There is then the problem of how to evaluate the contribution of each drug to
the final outcome, and this clearly requires statistical input to the design of
the study, rather than merely to the evaluation of the results.
Practical issues in the
use of crude cannabis versus pure cannabinoids
A number of differences in
the manner of use of marijuana and of pure THC and other cannabinoids will also
affect the design of comparative clinical trials. The first is the route of
administration: marijuana can be used only by inhalation of smoke or by mouth
(e.g., in brownies), whereas pure cannabinoids can be used by almost all
routes. For therapeutic trials, one would wish to use the most effective route
for each drug, and these are different. Therefore, in double blind comparison
trials, it may be necessary to include a placebo control for each route used,
e.g., smoked marijuana plus a placebo capsule, versus smoked placebo plus
a THC capsule. A second issue is the
choice of doses for each agent being compared. It is not sufficient to use the
same dose of THC in each form, because the route of administration, as already noted,
affects the pharmacokinetics, resulting in different rates of absorption,
different peak concentrations in plasma, and different time course of action.
Therefore it is necessary to use dosages that produce equivalent peak effects,
rather than identical amounts.
A related dosage problem is
that absorption is quite variable, both for smoking and for oral ingestion.
Smoking techniques can be standardized by adequate training of experimental
subjects, with respect to frequency, volume of draw, depth of inhalation, and
duration of retention of smoke in the chest, but it is questionable whether
this can be done satisfactorily in ill patients. No such training is possible
at all, with respect to absorption after oral ingestion.
International
perspective on medical use of marijuana
A number of major reviews
of the possible therapeutic uses of cannabis and cannabinoids have been carried
out in several countries in the past seven years. A report of the Royal
Pharmaceutical Society of Great Britain128 dealt with actual
protocols for proposed multicentre clinical trials of smoked marijuana vs. oral
THC for the treatment of postoperative
pain and of muscle spasm in multiple sclerosis. The other reports, however,
presented more general coverage of the nature of cannabis and cannabinoids,
their potential therapeutic uses, and their limitations. It is therefore
informative to review their conclusions briefly, to see what measure of
agreement or disagreement there is among them.
The report of the National
Drug Strategy of Australia43 concluded that there is good evidence
of the effectiveness of THC as an antiemetic, reasonable evidence for the potential
therapeutic use in glaucoma, and suggestive evidence for possible use as
an analgesic, an antiasthmatic agent, an anticonvulsant and an antispasticity
agent in multiple sclerosis. It called for properly controlled trials dealing
with these potential indications, as well as with the wasting syndrome and
depression in HIV/AIDS patients. However, all of these recommendations dealt
with pure synthetic cannabinoids, and not with clinical trials of smoked
marijuana.
The British Medical
Association Report129 recommended further clinical research to
establish suitable methods and routes of administration and optimal dosage for
therapeutic use in nausea and vomiting (including well-controlled comparisons
with ondansetron and other 5-HT3 antagonists); chronic refractory
spastic disorders; chronic, terminal, and postoperative pain; poorly controlled
epilepsy; strokes and CNS degenerative disorders; and glaucoma. It also recommended
further study of cannabinoid effects on the immune system, not with respect to
possible use as an immunosuppressant but rather, to see whether cannabinoids
are safe to use in patients with already compromised immune systems. It
specifically rejects the idea of therapeutic use of smoked marijuana or of
unstandardized herbal preparations of cannabis, and points out the potential
problems of cannabis tolerance and dependence in patients requiring long-term
therapy.
The report of a Select
Committee of the British House of Lords130 recommended clinical
trials of cannabis treatment in multiple sclerosis and chronic pain "as a
matter of urgency", but urged further research on alternative methods of
administration, such as sublingual, rectal, or aerosol-type inhalation, for
rapid absorption without the adverse effects of smoking. It also pointed out
the risks of acute intoxication, dependence and chronic health problems caused
by cannabis itself, and suggested that clinical trials of smoked marijuana
should be considered only under special circumstances (of unspecified type). It
suggested that one of the objectives of clinical trials should be to compare
crude cannabis with pure THC, using doses that provide the same amount of THC by the same route, to see whether
other constituennts of cannabis add anything to the therapeutic effect.
The report of the US
Institute of Medicine112 found good evidence for a useful analgesic
action, complementary to that of opioids. It also found good evidence for a
moderate antinauseant and antiemetic effect, again useful mainly as a
supplement to conventional treatment. The appetite stimulation effect was
considered "promising", again mainly as a supplement to megestrol
acetate. It recommended clinical trials of possible relief of muscle
spasticity, but considered that oral THC might be superior to inhalation,
because of the longer duration of action. It did not consider movement
disorders, epilepsy, or glaucoma to be promising areas for clinical studies
with cannabis. Finally, it recommended further research on development of safe,
reliable alternative delivery systems that could provide rapid onset of action;
trials of smoked marijuana should be limited to short-term use, and only for
those indications for which present evidence suggests a probable beneficial
effect.
The conclusions set out in
these reports have some important similarities and differences. All of them
consider smoking to be an undesirable method of administering cannabis for
therapeutic purposes, and recommend research on alternative methods of
administration for rapid onset without the risks associated with smoking. All
of them accept the antinauseant, antiemetic, appetite-stimulating, analgesic
and antispasticity effects as worthy of further clinical trials. All of them
recommend precise comparison of cannabis with pure THC or other cannabinoids. They
disagree about the justification for clinical trials of cannabinoids for
treatment of asthma, epilepsy and glaucoma. Most of them accept the validity of
clinical trials of smoked marijuana under special circumstances, primarily in
terminally ill patients or for a limited time only in others. However, the
Australian report refers only to pure cannabinoids, and a report of the
Netherlands Health Council131 rejects completely the idea of any
clinical use of crude cannabis, a view shared in a recent non-governmental
review in the UK12.
CONCLUSIONS
Though cannabis has a long
history of therapeutic use, in both traditional and Western medicine, it fell
into disuse almost a century ago when it was superseded by more stable,
reliable and effective new synthetic medications. The isolation and synthesis
of pure cannabinoids, including more potent synthetic derivatives, and the
discovery of cannabinoid receptors and their endogenous ligands, have renewed
the interest in potential medical uses. This has also been stimulated by the
claims of many cannabis smokers that their use of marijuana is for therapeutic
rather than hedonic purposes.
Pure tetrahydrocannabinol
is already approved for the relief of nausea and vomiting, and for stimulation
of appetite. The major claims for other uses include relief of pain, muscle
spasm, epilepsy and glaucoma. Both animal experiments and clinical observation
provide varying degrees of support for these claims, but most of the controlled
clinical observations have been with pure cannabinoids given by mouth, rather
than with smoked cannabis. Properly designed, controlled, double-blind trials
are needed to establish the efficacy for most of these claimed applications, to
compare the relative potencies and benefits of crude cannabis versus pure
cannabinoids for each, to compare both with existing therapies, to identify all
the potential adverse effects, and to assess alternative delivery methods, such
as inhalers or low-heat non-combustive volatilizers to deliver measured doses
of cannabinoids for rapid onset of action without the pulmonary hazards of
cannabis smoke. Until much of this information is available, it is premature to
recommend general use of cannabis or cannabinoids for these indications.
REFERENCES
1. Schultes RE. Random
thoughts and queries on the botany of cannabis. In: Joyce CRB, Curry SH, eds. The Botany and
Chemistry of Cannabis. London: J & A Churchill, 1970:11-38.
2. Commission of Inquiry
into the Non-Medical Use of Drugs (Le Dain Commission). Cannabis. Ottawa: Information Canada, 1972:11-25 and 125-126.
3. Adams IB, Martin BR.
Cannabis: pharmacology and toxicology in animals and humans. Addiction
1996;91:1585-1614.
4. Bouquet J. Contribution
à l'étude du chanvre indien. Lyon: Paul Legendre & Cie, 1912.
5. Indian Hemp Drugs
Commission (1893-1894) Report on Indian Hemp. Simla, Government Central
Printing Office, 1894.
6. Kalant OJ. Report of the
Indian Hemp Drugs Commission, 1893-94: A critical review. Int J Addictions
1972;7:77-96.
7. Moreau (de Tours) J.J.
Du Hachisch et de l'Aliénation Mentale. Paris: Masson, 1845.
8. Kalant OJ. Moreau,
Hashish, and hallucinations. Int J Addictions 1971;6:553-560.
9. O'Shaughnessy WB. On the
preparations of the Indian hemp, or Gunjah Cannabis indica. Prov Med J
Retro Med Sci 1843;5:343.
10. Walton, R.P. Marihuana.
America's New Drug Problem. New York: J B Lippincott, 1938.
11. Mikuriya TH. Marijuana
in medicine: past, present and future. California Med 1969;110:34-40.
12. Brown DT. The
therapeutic potential for cannabis and its derivatives. In: Brown DT, ed.
Cannabis: The Genus Cannabis. Amsterdam: Harwood Academic Publishers,
1998:175-222.
13. Fairbairn JW, Liebman
JA, Rowan MG. The stability of cannabis and its preparations on storage. J
Pharm Pharmacol 1976;28:1-7.
14. Todd AR. Hashish.
Experientia 1946;2:55-60.
15. Todd AR. Chemistry of
the hemp drugs. Nature 1940;146:829-830.
16. Adams R, Loewe S,
Jelinek C, Wolff H. Tetrahydrocannabinol homologs with marihuana activity. J Am
Chem Soc 1941;63:1971-1973.
17. Hollister LE, Gillespie
HK. Delta-8- and delta-9-tetrahydrocannabinol. Comparison in man by oral and
intravenous administration. Clin Pharmacol Ther 1973;14:353-357.
18. Karniol IG, Carlini EA.
Comparative studies in man and in laboratory animals on ?8- and ?9-trans-tetrahydrocannabinol.
Pharmacology 1973;9:115-126.
19. Mechoulam R, Braun P,
Gaoni Y. Syntheses of ?1-tetrahydrocannabinol and related
cannabinoids. J Am Chem Soc 1972;94:6159-6165.
20. Claussen U, Korte F.
Die Struktur zweier synthetischer Isomerer des Tetrahydrocannabinol. Z
Naturforsch 1966;21:594-595.
21. Devane WA, Dysarz FA,
Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a
cannabinoid receptor in rat brain. Mol Pharmacol 1988;34:605-613.
22. Devane WA, Hanus L,
Breuer A, Pertwee RG, Stevenson LA, et al. Isolation and structure of a brain constituent
that binds to the cannabinoid receptor. Science 1992;258:1946-1949.
23. Howlett AC.
Pharmacology of cannabinoid receptors. Ann Rev Pharmacol Toxicol
1995;35:607-634
24. Pertwee RG. The central
neuropharmacology of psychotropic cannabinoids. Pharmacol Ther 1987;36:189-261.
25. Jay WM, Green K.
Multiple-drop study of topically applied 1% ?9-tetrahydrocannabinol
in human eyes. Arch Ophthalmol 1983;101:591-593.
26. Green K. Marijuana
smoking vs cannabinoids for glaucoma therapy. Arch Ophthalmol 1998;116:1433-1437.
27. Wall ME, Sadler BM,
Brine D, Taylor H, Perez-Reyes M. Metabolism, disposition, and kinetics of ?9-tetrahydrocannabinol
in men and women. Clin Pharmacol Ther 1983;34:352-363.
28. Agurell S, Halldin M,
Lindgren JE, Ohlsson A, Widman M, Hollister L. Pharmacokinetics and metabolism
of ?-1-tetrahydrocannabinol and other cannabinoids with emphasis on man.
Pharmacol Rev 1986;38:21-43.
29. Martin BR, Cone EJ.
Chemistry and Pharmacology of cannabis. In: Kalant H, Corrigall WA, Hall W, Smart RG, eds. The Health
Effects of Cannabis. Toronto: CAMH, 1999:19-68.
30.
Mattes RD, Shaw LM, Edling-Owens J, Engelman K, ElSohly MA. Bypassing
the first-pass effect for the therapeutic use of cannabinoids. Pharmacol
Biochem Behav 1993;44:745-747.
31. Payne RJ, Brand SN. The
toxicity of intravenously used marihuana. J Am Med Assoc 1975;233:351-354.
32. Korte F, Haag M, Claussen U. Tetrahydrocannabinol-carbonsäure,
ein neuer Haschisch-Inhaltsstoff. Angew. Chem. 1966;77:862.
33. Claussen U, Korte F.
Über das Verhalten von Hanf und von ?9-6a,10a-trans-tetrahydrocannabinol
beim Rauchen. Liebigs Ann Chem 1968;713:162-165.
34. Azorlosa JL, Heishman
SJ, Stitzer ML, Mahaffey JM. Marijuana smoking: Effect of varying ?9-tetrahydrocannabinol
content and number of puffs. J Pharmacol Exp Ther 1992;261:114-122.
35. Azorlosa JL, Greenwald
MK, Stitzer ML. Marijuana smoking: Effects of varying puff volume and
breathhold duration. J Pharmacol Exp Ther 1995;272:560-569.
36. Kreuz DS, Axelrod J.
Delta-9-tetrahydrocannabinol: localization in body fat. Science
1973;179:391-393.
37. Nahas GG. Marihuana:
toxicity and tolerance. In: Richter RW, ed. Medical Aspects of Drug Abuse. Baltimore: Harper & Row, 1975:16-36
38. Ohlsson A, Lindgren
J-E, Wahlen A, Agurell S, Hollister LE, Gillespie HK. Single dose kinetics of
deuterium-labeled ?1-tetrahydrocannabinol in heavy and light
cannabis users. Biomed Mass Spectrometry 1982;9:6-10.
39. Klonoff H. Acute
psychological effects of marihuana in man, including acute cognitive,
psychomotor and perceptual effects on driving. In: Fehr KO, Kalant H, eds.
Cannabis and Health Hazards. Toronto: ARF Books, 1983:433-474.
40. Chaperon F, Thiebot MH.
Behavioral effects of cannabinoid agents in animals. Crit Rev Neurobiol
1999;13:243-281.
41. Siemens AJ. Effects of cannabis
in combination with ethanol and other drugs. In: Petersen RC, ed. Marijuana
Research Findings: 1980. NIDA Res Monogr Ser. 31. Washington, DC: DHHS/USPHS, 167-198.
42. Hollister LE.
Interactions of ?9-tetrahydrocannabinol with other drugs. Ann NY Acad
Sci 1976;281:212-218.
43. Hall W, Solowij N,
Lemon J. The health and psychological consequences of cannabis use. Canberra: Australian Govt Publishing
Service, 1994:41-60.
44. Beardsley PM, Kelly TH.
Acute effects of cannabis on human behavior and central nervous system
functions. In: Kalant H, Corrigall WA, Hall W, Smart RG, eds. The Health Effects of
Cannabis. Toronto: CAMH, 1999:127-169.
45. Smiley A. Marijuana:
on-road and driving-simulator studies. In: Kalant H, Corrigall WA, Hall W, Smart RG, eds. The Health
Effects of Cannabis. Toronto:CAMH, 1999:171-191.
46. Yesavage JA, Leirer VO,
Denari M, Hollister LE. Carry-over effects of marijuana intoxication on
aircraft pilot performance: A preliminary report. Am J Psychiatry
1985;142:1325-1329.
47. Solowij N. Long-term
effects of cannabis on the central nervous system. I. Brain function and
neurotoxicity. II. Cognitive functioning. In: Kalant H, Corrigall WA, Hall W, Smart RG, eds. The Health
Effects of Cannabis. Toronto: CAMH, 1999:195-265.
48. Milstein SL, MacCannell
K, Karr G, Clark S. Marijuana-produced changes in pain tolerance. Experienced
and non-experienced subjects. Int Pharmacopsychiatry 1975;10:177-182.
49. Martin BR, Lichtman AH.
Cannabinoid transmission and pain perception. Neurobiol Dis 1998;5:447-461.
50. Meng ID, Manning BH,
Martin WJ, Fields HL. An analgesia circuit activated by cannabinoids. Nature
1998;395:381-383.
51. Fuentes JA, Ruiz-Gayo
M, Manzanares J, Reche I, Corchero J. Cannabinoids as potential new analgesics.
Life Sci 1999;65:675-685.
52. Martin WJ, Coffin PO,
Attias E, Balinsky M, Tsou K, Walker JM. Anatomical basis for
cannabinoid-induced antinociception as revealed by intracerebral
microinjections. Brain Res 1999;822:237-242.
53. Walker JM, Hohmann AG,
Martin WJ, Strangman NM, Huang SM, Tsou K. The neurobiology of cannabinoid
analgesia. Life Sci 1999;65:665-673.
54. Ko MC, Woods JH. Local
administration of ?9-tetrahydrocannabinol attenuates
capsaicin-induced thermal nociception in rhesus monkeys: a peripheral
cannabinopid action. Psychopharmacology 1999;143:322-326.
55. Lichtman AH, Martin BR.
The selective cannabinoid antagonist SR 141716A blocks cannabinoid-induced
antinociception in rats. Pharmacol Biochem Behav 1997;57:7-12.
56. Hartel CR. Therapeutic
uses of cannabis and cannabinoids. In: Kalant H, Corrigall WA, Hall W, Smart RG, eds. The Health
Effects of Cannabis. Toronto: CAMH, 1999:461-474.
57. Jones RT, Benowitz N.
The 30-day trip - Clinical studies of cannabis tolerance and dependence. In:
Braude MC, Szara S, eds. Pharmacology of Marijuana. New York: Academic Press, 1976:vol. 2,
627-642.
58. Mendelson JH. Marijuana
use: Biologic and behavioral aspects. Postgrad Med 1976;60:111-115.
59.
Mattes RD, Engelman K, Shaw LM, ElSohly M. Cannabinoids and appetite
stimulation. Pharmacol Biochem Behav 1994;49:187-195.
60.
Sofia RD, Solomon TA, Barry H, III. Anticonvulsant activity of ?9-tetrahydrocannabinol
compared with three other drugs. Eur J Pharmacol 1976;35:7-16.
61. Corcoran ME, McCaughran
JA Jr, Wada JA. Antiepileptic and prophylactic effects of tetrahydrocannabinols
in amygdaloid kindled rats. Epilepsia 1978;19:47-55.
62. Chiu P, Olsen DM, Borys
HK, Karler R, Turkanis SA. The influence of cannabidiol and ?9-tetrahydrocannabinol
on cobalt epilepsy in rats. Epilepsia 1979;20:365-375.
63. Karler R, Turkanis SA.
The cannabinoids as potential antiepileptics. J Clin Pharmacol
1981;21(Suppl):437S-448S.
64. Consroe P, Benedito MA,
Leite JR, Carlini EA, Mechoulam R. Effects of cannabidiol on behavioral
seizures caused by convulsant drugs or current in mice. Eur J Pharmacol
1982;83:293-298.
65. Consroe P. Brain
cannabinoid systems as targets for the therapy of neurological disorders.
Neurobiol Dis 1998;5:534-551.
66. Chesher G, Hall W.
Effects of cannabis on the cardiovascular and gastrointestinal systems. In:
Kalant H, Corrigall W, Hall W, Smart RG, eds. The Health Effects of Cannabis. Toronto:CAMH, 1999:437-458.
67. Tashkin DP. Cannabis
effects on the respiratory system. In: Kalant H, Corrigall WA, Hall W, Smart RG, eds. The Health
Effects of Cannabis. Toronto:CAMH, 1999:313-345.
68. Klein TW. Cannabis and
immunity. In: Kalant H, Corrigall WA, Hall W, Smart Rg, eds. The Health Effects of
Cannabis. Toronto:CAMH, 1999:349-373.
69. Caiaffa WT, Vlahov D,
Graham NM, Astemborski J, Solomon L, Nelson KE, Muñoz A. Drug smoking,
Pneumocystis carinii pneumonia, and immunosuppression increase risk of
bacterial pneumonia in human immunodeficiency virus-seropositive injection drug
users. Am J Respir Crit Care Med 1994;150:1493-1498.
70. Denning DW, Follansbee
SE, Scolaro M, Norris S, Edelstein H, Stevens DA. Pulmonary aspergillosis in
the acquired immunodeficiency syndrome. N Engl J Med 1991;324:654-662.
71. Marks WH, Florence L,
Lieberman J, Chapman P, Howard D, Roberts P, Perkinson D. Successfully treated
invasive pulmonary aspergillosis associated with smoking marijuana in a renal
transplant recipient. Transplantation 1996;61:1771-1774.
72. Sutton S, Lum BL, Torti
FM. Possible risk of invasive pulmonary aspergillosis with marijuana use during
chemotherapy for small cell lung cancer. Drug Intell Clin Pharm
1986;20:289-291.
73. Didcott P, Reilly D,
Swift W, Hall W. Long-term cannabis users on the New South Wales North Coast.
NDARC Monograph No. 30. Sydney, Australia:NDARC, 1997:36-41.
74. Swift W, Hall W,
Copeland J. Cannabis dependence among long-term users in Sydney, Australia.
NDARC Tech Rep No. 47. Sydney, Australia:NDARC, 1997.
75. Crowley TJ, Macdonald
MJ, Whitmore EA, Mikulich SK. Cannabis dependence, withdrawal, and reinforcing
effects among adolescents with conduct symptoms and substance use disorders.
Drug Alcohol Depend 1998;50:27-37.
76. Wiesbeck GA, Schuckit
MA, Kalmijn JA, Tipp JE, Bucholz KK, Smith TL. An evaluation of the history of
a marijuana withdrawal syndrome in a large population. Addiction
1996;91:1469-1478.
77. Haney M, Ward AS, Comer
SD, Foltin RW, Fischman MW. Abstinence symptoms following oral THC administration to humans.
Psychopharmacology 1999;141:385-394.
78. Haney M, Ward AS, Comer
SD, Foltin RW, Fischman MW. Abstinence symptoms following smoked marijuana in
humans. Psychopharmacology 1999;141:395-404.
79. Aceto MD, Scates SM,
Lowe JA, Martin BR. Cannabinoid precipitated withdrawal by the selective
cannabinoid receptor antagonist, SR 141716A. Eur J Pharmacol 1995;282:R1-R2
80. Negrete JC. Cannabis
and schizophrenia. Br J Addiction 1989;84:349-351.
81. Channabasavanna SM,
Paes M, Hall W. Mental and behavioral disorders due to cannabis use. In: Kalant
H, Corrigall WA, Hall W, Smart RG, eds. The Health
Effects of Cannabis. Toronto:CAMH, 1999:269-290.
82. Baigent M, Holme G,
Hafner RJ. Self reports of the interaction between substance abuse and
schizophrenia. Austral NZ J Psychiatry 1995;29:69-74.
83. Fried PA, Watkinson B,
Gray R. Differential effects on cognitive functioning in 9 to 12 year olds
prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol
1998;20:293-306.
84. Fried PA, Watkinson B.
Visuoperceptual functioning differs in 9- to 12-year olds prenatally exposed to
cigarettes and marihuana. Neurotoxicol Teratol 2000;22:11-20.
85. Tashkin DP, Coulson AH,
Clark VA, Simmons M, Bourque LB, Duann S, Spivey GH, Gong H. Respiratory
symptoms and lung function in habitual, heavy smokers of marijuana alone,
smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers. Am
Rev Resp Dis 1987;135:209-216.
86. Bloom JW, Kaltenborn
WT, Paoletti P, Camilli A, Lebowitz MD. Respiratory effects of non-tobacco
cigarettes. Br Med J 1987;295:1516-1518.
87. Van Hoozen BE, Cross
CE. Marijuana: Respiratory tract effects. Clin Rev Allergy Immunol
1997;15:243-269.
88. Donald PJ. Advanced
malignancy in the young marijuana smoker. Adv Exp Med Biol 1991;288:33-46.
89. Sridhar KS, Raub WA Jr,
Weatherby NL, Metsch LR, Surratt HL, Inciardi JA, Duncan RC, Anwyl RS, McCoy
CB. Possible role of marijuana smoking as a carcinogen in the development of
lung cancer at a young age. J Psychoactive Drugs 1994;26:285-288.
90. Barsky SH, Roth MD,
Kleerup EC, Simmons M, Tashkin DP. Histopathologic and molecular alterations in
bronchial epithelium in habitual smokers of marijuana, cocaine, and/or tobacco.
J Natl Cancer Inst 1998;90:1198-1205.
91. Sidney S, Quesenberry
CP, Friedman GD, Tekawa IS. Marijuana use and cancer incidence (California, United States). Cancer Causes Control
1997;8:722-728.
92. Zhang Z-F, Morgenstern
H, Spitz MR, Tashkin DP, Yu G-P, Marshall JR, Hsu TC, Schantz SP. Marijuana use
and increased risk of squamous cell carcinoma of the head and neck. Cancer
Epidemiol Biomark Prev 1999;8:1071-1078.
93. Murphy L. Cannabis
effects on endocrine and reproductive function. In: Kalant H, Corrigall WA, Hall W, Smart RG, eds. The Health
Effects of Cannabis. Toronto:CAMH, 1999:377-400.
94. Jain AK, Ryan JR,
McMahon FG, Smith G. Evaluation of intramuscular levonantrodol and placebo in
acute postoperative pain. J Clin Pharmacol 1981;21:320S-326S.
95. Raft D, Gregg J, Ghia
J, Harris L. Effects of intravenous tetrahydrocannabinol on experimental and
surgical pain. Psychological correlates of the analgesic response. Clin
Pharmacol Ther 1977;21:26-33.
96. Noyes R Jr, Brunk SF,
Avery DH, Canter A. The analgesic properties of delta-9-tetrahydrocannabinol
and codeine. Clin Pharmacol Ther 1975;18:84-89.
97. Holdcroft A, Smith M,
Jacklin A, Hodgson H, Smith B, Newton M, Evans F. Pain relief with oral cannabinoids
in familial Mediterranean fever. Anaesthesia 1997;52:483-486.
98. Herzberg U, Eliav E,
Bennett GJ, Kopin IJ. The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity
cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett 1997;221:157-160.
99. Russo E. Cannabis for
migraine treatment: the once and future prescription? An historical and
scientific review. Pain 1998;76:3-8.
100. Hirst RA, Lambert DG,
Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. Br J Anaesthesia
1998;81:77-84.
101. Burstein SH. The
cannabinoid acids: nonpsychoactive derivatives with therapeutic potential.
Pharmacol Ther 1999;82:87-96.
102. Pop E, Liu ZZ,
Brewster ME, Barenholz Y, Korablyov V, Mechoulam R, Nadler V, Biegon A.
Derivatives of Dexanabinol. I. Water-soluble salts of glycinate esters.
Pharmaceut Res 1996;13:62-69.
103. Schon F, Hart PE,
Hodgson TL, Pambakian AL, Ruprah M, Williamson EM, Kennard C. Suppression of
pendular nystagmus by smoking cannabis in a patient with multiple sclerosis.
Neurology 1999;53:2209-2210.
104. Consroe P, Musty R,
Rein J, Tillery W, Pertwee R. The perceived effects of smoked cannabis on
patients with multiple sclerosis. Eur Neurol 1997;38:44-48.
105. Greenberg HS, Werness
SA, Pugh JE, Andrus RO, Anderson DJ, Domino EF. Short-term effects of smoking
marijuana on balance in patients with multiple sclerosis and normal volunteers.
Clin Pharmacol Ther 1994;55:324-328.
106. Petro DJ, Ellenberger
C Jr. Treatment of human spasticity with ?9-tetrahydrocannabinol. J
Clin Pharmacol 1981'21:413S-416S.
107. Ungerleider JT,
Andrysiak T, Fairbanks L, Ellison GW, Myers LW. Delta-9-THC in the treatment of spasticity
associated with multiple sclerosis. Adv Alcohol Substance Abuse 1987;7:39-50.
108. Martyn CN, Illis LS,
Thom J. Nabilone in the treatment of multiple sclerosis. Lancet 1995;345:579.
109. Brenneisen R, Egli A,
ElSohly MA, Henn V, Spiess Y. The effect of orally and rectally administered ?9-tetrahydrocannabinol
on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther
1996;34:446-452.
110. Cunha JM, Carlini EA,
Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, Mechoulam
R. Chronic administration of cannabidiol to healthy volunteers and epileptic
patients. Pharmacology 1980;21:175-185.
111. Ames FR.
Anticonvulsant effect of cannabidiol. S Afr Med J 1986; 69:14.
112. Joy JE, Watson SJ Jr,
Benson JA Jr, eds. Marijuana and Medicine: Assessing the Science Base. Washington, DC:Natl Academy Press, 1999.
113. Chiang C-WN, Barnett
G. Marijuana effect and delta-9-tetrahydrocannabinol plasma level. Clin
Pharmacol Ther 1984:36:234-238.
114. Cone EJ, Huestis MA.
Relating blood concentrations of tetrahydrocannabinol and metabolites to
pharmacologic effects and time of marijuana usage. Therap Drug Monitoring
1993;15:527-532.
115. Siemens AJ, Kalant H,
Khanna JM, Marshman J, Ho G. Effect of cannabis on pentobarbital-induced
sleeping time and pentobarbital metabolism in the rat. Biochem Pharmacol
1974;23:477-488.
116. Bornheim LM, Everhart
ET, Li J, Correia MA. Induction and genetic regulation of mouse hepatic
cytochrome P450 by cannabidiol. Biochem Pharmacol 1994;48:161-171.
117. Fernandes M, Schabarek
A, Coper H, Hill R. Modification of ?9-THC-actions by cannabinol and
cannabidiol in the rat. Psychopharmacologia (Berl) 1974;38:329-338.
118. Frizza J, Chesher GB,
Jackson DM, Malor R, Starmer GA. The effect of ?9-tetrahydrocannabinol,
cannabidiol, and cannabinol on the anaesthesia induced by various anaesthetic
agents in mice. Psychopharmacology 1977;55:103-107.
119. Hine B, Torrelio M,
Gershon S. Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence
in morphine-dependent rats. Res Comm Chem Pathol Pharmacol 1975;12:185-188.
120. Karniol IG, Carlini
EA. Pharmacological interaction between cannabidiol and ?9-tetrahydrocannabinol.
Psychopharmacologia (Berl) 1973;33:53-70.
121. Karniol IG, Shirakawa
I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects
of ?9-tetrahydrocannabinol in man. Eur J Pharmacol 1974;28:172-177.
122. Hiltunen AJ, Jarbe TU.
Cannabidiol attenuates ?9-tetrahydrocannabinol-like discriminative
stimulus effects of cannabinol. Eur J Pharmacol 1986;125:301-304.
123. Brady KT, Balster RL.
The effects of ?9-tetrahydrocannabinol alone and in combination with
cannabidiol on fixed-interval performance in rhesus monkeys. Psychopharmacology
1980;72:21-26.
124. Borgen LA, Davis WM.
Cannabidiol interaction with ?9-tetrahydrocannabinol. Res Comm Chem
Pathol Pharmacol 1974;7:663-670.
125. Dalton WS, Martz R, Lemberger L, Rodda BE,
Forney RB. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects.
Clin Pharmacol Ther 1976;19:300-309.
126. Hollister LE,
Gillespie HK. Interactions in man of delta-9-tetrahydrocannabinol. II.
Cannabinol and cannabidiol. Clin Pharmacol Ther 1975;18:80-83.
127. ten Ham M, de Jong Y.
Absence of interaction between ?9-tetrahydrocannabinol (?9-THC) and cannabidiol (CBD) in aggression, muscle control, and
body temperature experiments in mice. Psychopharmacologia (Berl)
1975;41:169-174.
128. Royal Pharmaceutical
Society of Great Britain. Launch of the Protocols for the
Clinical Trials of Cannabinoids. London:Royal Pharmaceut Soc 1999.
129. British Medical
Association. Therapeutic uses of cannabis. Amsterdam: Harwood Academic Publishers, 1997.
130. House of Lords, Select
Committee on Science and Technology, Ninth Report. Cannabis: The Scientific and
Medical Evidence. London: Parliament Stationery Office,
1998.
131. Health Council of the Netherlands, Standing Committee on Medicine.
Marihuana as Medicine. Rijswijk: Health Council of the Netherlands, 1996. Cited in ref. 112.
Table 1. Relative
affinities of various cannabinoids for CB1 and CB2
cannabinoid receptors
|
CB1
|
CB2
|
| Agonists |
|
|
< 9-THC, < x-THC
|
+++
|
+++
|
nabilone
|
++++
|
++++
|
levonantrodol
|
++++
|
++++
|
WIN 55,212
|
++
|
++++
|
cannabinol
|
+
|
++
|
anandamide
|
++
|
+
|
Antagonists
|
|
|
SR
141716A
|
++++
|
-
|
SR 144528
|
-
|
++++
|
Legends for Figures
Figure 1. Relationships
between crude cannabis products and pure cannabinoids.
Figure 2. Structures of the
major cannabinoids, including naturally occurring compounds, synthetic analogs
or derivatives, and endogenous cannabinoid-like compounds in the mammalian
organism. Arrows indicate closest resemblances, not actual lines of synthesis.
