Title: Biomedical benefits of cannabinoids?
ISSN: 1355-6215
Abstract
Cannabinoids appear to be of therapeutic value as antiemetics,
antispasmodics, analgesics and appetite stimulants and may have
potential uses in epilepsy, glaucoma and asthma. Scientific evidence
for any of these indications, except for antiemetic effects, is
extremely sparse and claims for clinical utility are largely based on
anecdotal reports. Furthermore, the mechanisms of action of any of the
therapeutic effects are unknown. This paper reviews the clinical
trials which have been carried out with cannabinoids including
Delta[sup 9]-tetrahydrocannabinol (THC) and synthetic cannabinoids
such as nabilone and levonantradol, and discusses the advantages and
adverse effects of cannabinoids in clinical use. The place of
cannabinoids in modern medicine remains to be properly evaluated, but
present evidence suggests that they could be valuable, particularly as
adjuvants, for symptom control in a range of conditions for which
standard drugs are not fully satisfactory.
Historical background
Cannabis has been used medicinally for thousands of years. It was
known to the Sumerians, Assyrians, Chinese and Indians as far back as
the second millennium BC and recommended for many ailments including
malaria, constipation, rheumatic pains and female disorders.(n1-n3)
The drug entered mainstream western medicine following the advocacy of
O'Shaugnessy,(n4) who had observed its use in India and was impressed
by its muscle relaxant, anticonvulsant, analgesic and antiemetic
properties. It was widely prescribed in the 19th century but its
popularity waned as more reliable drugs became available. However,
cannabis could be prescribed (as a tincture) in the United Kingdom
until 1971 when it was classified under Schedule 1 of the Misuse of
Drugs Act as having no therapeutic benefit. The synthetic cannabinoids
nabilone in the United Kingdom, and dronabinol in the United States,
remained licensed for the specific indication of vomiting due to
chemotherapy.
Interest in the biomedical benefits of cannabis has been renewed
recently following anecdotal reports of efficacy in a wide variety of
disorders from multiple sclerosis to glaucoma.(n3) These reports,
backed by an extremely limited amount of scientific evidence (see
Table 1), have led to recommendations that clinical research should be
implemented on the therapeutic uses of cannabinoids. A Clinical
Cannabinoid Group has been set up to develop guidelines for such
research.(n5)
This review is based on a Medline search of all papers on the
pharmacology, clinical and therapeutic effects of cannabis and
cannabinoids 1980-98, supplemented by comprehensive books and
compendia and standard books and papers from the older literature.
Relevant books and papers were hand-searched for additional
references. Further information was supplied from the Department of
Health, particularly a report on therapeutic aspects of cannabinoids
by Dr P. Robson(n6) and from colleagues. The search was originally
conducted for reports commissioned by the Department of Health(n7)and
the British Medical Association,(n5) but has been updated. The papers
quoted in the present review were selected from a very large
bibliography as having direct clinical relevance. The review is not
claimed to be comprehensive: it is largely confined to papers in the
English language and where possible to clinical rather than
preclinical or animal studies. Nevertheless, it is hoped that a
balanced overall picture of the area is provided.
Pharmacology
The medicinal properties of cannabis are due to its content of
cannabinoids, which are unique to the plant species Cannabis sativa.
Over 60 cannabinoids, chemically aryl-substituted meroterpenes,(n8)
have been identified. The pharmacology of most of these is unknown but
the most potent psychoactive agent is Delta[sup9]-tetrahydrocannabinol (THC). Some plant cannabinoids are shown in Fig. 1. Not all are psychoactive but some have additive, synergistic or inhibitory interactions with THC. In addition, several synthetic
cannabinoids are available for medical use and research purposes
(Table 2).
Cannabinoids interact with specific cannabinoid receptors in the
body.
CB[sub 2] receptors belong to the class of G-protein coupled
receptors
which act on second messenger systems affecting cyclic AMP formation
and Ca[sup ++] and K[sup +] ion transport.(n12) Natural ligands for
these receptors appear to be a family of anandamides (named after the
Sanskrit word for bliss, ananda).(n13) Anandamides are arachidonyl
acid derivatives related to prostaglandins. The normal physiological
functions of the cannabinoid/anandamide system are not known but may
include modulating effects on mood, memory and cognition, sensory
perception and pain, sleep, appetite, temperature control and immune
responses. Pharmacological, physiological and clinical implications
are reviewed by Pertwee.(n14)
Medicinal uses
Medicinal uses of cannabis and cannabinoids have recently been
reviewed by the British Medical Association(n5) and by several other
authors.(n6, n15-n17) Cannabinoids appear to be of therapeutic value
as antiemetics, antispasmodics, analgesics and appetite stimulants and
may have potential use in epilepsy, glaucoma and asthma. However, for
most of these indications (apart from antiemetic effects) the
scientific evidence is extremely sparse; there have been few if any
large scale controlled trials and claims for clinical utility are
based largely on anecdotal reports. Clinical trials that have been
undertaken are limited by small sample size, lack of statistical
power, use of different cannabis or cannabinoid preparations and
heterogeneous patient groups. Furthermore, the mechanisms of action of
any of the medicinal effects are not understood.
Cannabinoids as anti-emetics
Nausea and vomiting caused by antineoplastic chemotherapy "is at best
miserable and at worst so disabling and demoralising as to lead to
refusal of treatment".(n18) With some agents (including mustine,
dacarbazine, cisplatin, cyclophosphamide, doxorubicin and high dose
methotrexate) these symptoms are so common that anti-emetic drugs are
routinely given before and after treatment, often with the addition of
dexamethasone and lorazepam. Standard anti-emetic treatment has been
with dopamine receptor antagonists such as phenothiazines,
metoclopramide and domperidone. These drugs are moderately although
not completely effective and may produce dystonic reactions and other
adverse effects. Selective serotonin 5-HT[sub 3] receptor antagonists
have been introduced relatively recently but are expensive, may have
to be administered intravenously, and can cause constipation,
headache, hypersensitivity reactions, altered liver function and
dysrthythmias.(n19)
The anti-emetic efficacy of the synthetic cannabinoids nabilone and
THC (as the synthetic dronabinol) was investigated extensively, mostly
in the 1980s, in patients receiving a variety of cytotoxic drugs (see
references(n5,n17,n20-n23) for reviews). The evidence from a large
number of controlled trials is that oral nabilone (2mg 6-12-hourly)
and THC (5-15mg/m[sup 2]t.d.s. or q.d.s.) can be effective and are
superior to placebo.(n24-n27) Most studies indicate that they are more
effective than dopamine receptor antagonists;(n18, n28-n38) some
report equal effectiveness,(n24, n39-n41) while a few have found THC
to be less effective than standard drugs or placebo,(n42) especially
for patients on doxorubicin or cyclophosphamide(n43) or
cisplatin.(n44)
Another synthetic cannabinoid which has been tested as an anti-emetic
is levonantradol.(n45, n46) This agent appeared to have similar
efficacy to phenothiazines but produced an unacceptably high incidence
of somnolence and dysphoria. However, Delta[sup 8]-THC looks
promising. This cannabinoid, which is easier and cheaper to synthesize
than Delta[sup 9]-THC, was found to be completely effective in
preventing vomiting due to antineoplastic therapy in eight
children.(n47) It produced minimal adverse effects and was superior to
metoclopramide. Further trials are proceeding. Combinations of THC or
nabilone with prochlorperazine were found to improve anti-emetic
effectiveness while reducing adverse effects.(n42, n48, 49) Finally, a
few investigators(n27, n50, n51) and a number of anecdotal reports(n3)
have found smoked cannabis to be more effective than oral THC,
possibly because of better absorption.
Adverse effects are frequent with both nabilone and THC although they
are not usually severe or dangerous. The most common unwanted effect
is sedation which occurs in over 50% of patients. Other common effects
are dry mouth, ataxia, confusion, difficulties in concentration and
dysphoria. An incidence of "intolerable" dysphoria of about 10% is
reported for nabilone, possibly slightly lower for THC and higher for
levonantradol.(n22) A few patients report euphoria or
depersonalization and hallucinations and psychotic reactions occur
rarely. Systemic effects include postural hypotension and tachycardia.
Although such reactions may cause discontinuation in a minority,
patients often prefer cannabinoids to standard anti-emetic drugs.(n29)
Although cannabinoids have proven effectiveness as anti-emetics for
vomiting cause by cytotoxic agents in patients (including children)
with a variety of cancers, there remain areas which need further
investigation. First, there have been no comparisons between
cannabinoids and the specific 5-HT[sub 3] antagonists (ondansetron,
granisetron, tropisetron). Secondly, optimal dosages, schedules of
administration and effectiveness against different cytotoxic agents
have not been established. Thirdly, the use of drug combinations has
not been explored. It is possible that the addition of cannabinoids as
adjuvants to other anti-emetics could add to efficacy while allowing
the use of lower doses and minimizing adverse effects. Careful
preparation and explanation may also help to limit dysphoric
reactions; patients receiving cytotoxic therapy are ill, often
elderly, and unprepared for the psychological effects of cannabinoids.
Fourthly, trials with other cannabinoids, such as Delta[sup 8]STHC are
indicated. Finally, cannabinoids could be investigated in other types
of nausea and vomiting such as that due to opioids in pain conditions
and patients with AIDS.
Cannabinoids in spastic disorders
Many of the most distressing symptoms associated with spastic
disorders such as multiple sclerosis, spinal cord injury and cerebral
palsy are not well controlled with existing drugs. Such symptoms
include recurrent painful muscle spasms, various combinations of
weakness, tremor, dystonia and ataxia, acute and chronic pain
syndromes and impaired bladder and bowel control. Muscle relaxants,
analgesics and cholinergic or anticholinergic agents often give only
partial relief or unacceptable side effects. Furthermore, many
patients do not receive specialized treatment or adequate trials of
various drug combinations. Anecdotally,(n49-n58) cannabis relieves
many of these intractable symptoms and it is perhaps not surprising
that the commonest neurological causes of taking illicit cannabis are
multiple sclerosis and spinal cord injury.(n59, n60)
Despite its reputation among patients, there are only five published
reports of double or single blind placebo controlled studies of
cannabis or cannabinoids in multiple sclerosis, involving a total of
only 41 patients world-wide. Petro & Ellenberger(n61) gave single oral
doses of 5 or 10 mg THC to nine patients and noted a significant
reduction in objectively rated spasticity scores compared with
placebo. Clifford(n62) studied eight patients who received 5-15mg THC
orally 6 hourly for up to 18 hours. Five patients showed mild
subjective but not objective improvement in tremor and well-being
after THC and two showed subjective and objective improvement in
tremor but not ataxia or other symptoms. Ungerleider et al.(n63) gave
13 patients (who had proved refractory to baclofen, dantrolene and
diazepam) oral THC 2.5-15mg daily or b.d. for 5 days and found
significant subjective improvement overall in spasticity at doses of
7.5mg THC or greater, compared with placebo, but some patients got
worse. There was no change in objective measures of weakness,
spasticity, coordination, gait or reflexes. Martyn et al.(n64) studied
a single patient who received oral nabilone (1 mg on alternate days)
or placebo for two periods of 4 weeks each. The patient noted
improvement in general wellbeing, muscle spasms and frequency of
nocturia during the periods on nabilone (Fig. 2). Less encouraging
results were reported by Greenberg et al.,(n65) who observed the
effects of smoking cannabis in a cigarette containing 1.54% THC in 10
patients with multiple sclerosis and 10 normal subjects. Cannabis
impaired posture and balance in all subjects, causing greater
impairment in the patients, although some reported subjective
improvement.
Patients with spasticity due to spinal cord injuries or cerebral palsy
often have painful muscle cramps and impaired bladder control. There
appear to have been no controlled trials of cannabis or cannabinoids
in these disorders, but a few questionnaire surveys(n66, n67) suggest
that cannabis may be helpful for some but not all patients. Dunn &
Davies(n66) questioned 10 patients with spinal cord injury, of whom
five noted that cannabis improved spasticity but three reported
worsening of bladder symptoms. Twenty-one of 24 patients who replied
to a questionnaire sent to 48 patients reported that cannabis
decreased spasticity.(n67) Isolated case reports record that cannabis
relieved pain and muscle spasms in two patients with spinal cord
injury(n68) and that oral THC (5 mg) had a beneficial effect on pain
and spasticity in one.(n69)
With regard to movement disorders, cannabis appeared to be of no
benefit to patients with Parkinson's disease(n70) or parkinsonism
co-existing with dystonia in whom tremor and hypokinaesia were
aggravated.(n71) Oral cannabidiol (100-600 mg daily for 6 weeks)
improved dystonia in five patients with various dystonias(n72) but had
no effect in 15 patients with Huntington's disease.(n73)
Patients who take cannabis illicitly and report beneficial effects are
clearly a self-selected group. The results of controlled studies, few
though they are, are equivocal. Some patients appear to benefit but in
others there is no effect and some symptoms, such as ataxia and muscle
weakness, may be worsened. Ungerleider et al.(n63) reported a high
incidence of adverse reactions to THC at doses that were adequate to
relieve spasticity, affecting all but one patient at the 7.5 mg dose.
Side effects consisted of weakness, dry mouth, dysphoria, mental
clouding and other psychological effects. Clifford(n62) and Greenberg
et al.(n65) also reported psychological effects, including a "high" or
dysphoria in patients with multiple sclerosis receiving cannabinoids.
Nevertheless, the available evidence indicates a need for further
investigations into the value of cannabinoids (nabilone, THC and
perhaps more selective synthetic cannabinoids(n59) in spastic
disorders, particularly as present drugs are often unsatisfactory.
Cannabinoids seem most promising for muscle spasms and possibly tremor
and bladder control, and they may find a place as adjuvant drugs in
selected patients. Large controlled trials with carefully recruited
patients and accurate subjective and objective measurements of
efficacy are required. Treatment would need to be long-term and a
further problem which requires study in chronic illness is the
development of tolerance to cannabinoids.
Cannabinoids in pain conditions
Pain, particularly neuropathic pain, is often poorly controlled by
available analgesics, antiinflammatory agents, anticonvulsants or
antidepressants and the use of these drugs is sometimes limited by
adverse effects. New drugs with analgesic efficacy and minimal
toxicity are needed, and some claims have been made for cannabinoids
in this context. In animal models many cannabinoids have
anti-inflammatory and analgesic properties which appear to be mediated
by non-opioid mechanisms.(n59, n73) There is some anecdotal evidence
that cannabis alleviates various types of pain in man(n3) but very few
controlled trials.
Noyes et al.(n74, n75) carried out two double-blind placebo-controlled
trials in patients with cancer pain. In the first,(n69) 10 patients
received oral THC in a range of doses. Significant pain relief
compared with placebo was obtained with doses of 15 mg and 20 mg THC;
the analgesic effect peaked at 3 hours and lasted over 6 hours. In the
second study(n75) the effect of oral THC (10 mg and 20mg) was compared
with oral codeine 60mg and 120 mg. THC 20 mg and codeine 120 mg gave
significant and equivalent pain relief. In a single patient with
spinal cord injury 5 mg THC and codeine 50mg similarly gave equal pain
relief.(n69) In a controlled study of postoperative or trauma pain in
56 patients, levonantradol given intramuscularly provided significant
pain relief lasting over 6 hours after doses of 2.5mg or 3mg(n71) A
few reports have described relief of phantom limb pain after
cannabis.(n65, n77)
In contrast, no significant analgesic effect was found with
intravenous THC in 10 patients undergoing dental surgery(n78) and oral
cannabidiol provided no pain relief in 10 patients with chronic
neuropathic pain.(n79) Marked sedation was a common side effect of
cannabinoids in all the pain studies but other psychological effects
were minimal.
Cannabinoids thus appear to have a potential for pain relief with a
potency similar to that of codeine. Further research is needed, but
they may prove to be helpful, probably as adjuvant drugs, in chronic
and terminal pain and for various neuropathic pains, such as phantom
limb pain, not well-controlled by standard analgesics. It is
permissible at present to prescribe nabilone and THC for intractable
pain.
Cannabinoids as appetite stimulants
Acute doses of cannabis stimulate appetite, although with chronic use
the effect disappears.(n80) The anti-emetic effects may allow eating
and prevent weight loss in patients undergoing cancer chemotherapy and
these effects combined with appetite stimulation may benefit patients
with AIDS-related diseases, many of whom are receiving antiviral drugs
or have other illnesses which cause anorexia, nausea and vomiting. An
open study of 10 patients with AIDS-related disease receiving
antiviral therapy found that THC given daily over 5 months arrested
the progressive weight loss observed in these patients prior to
treatment.(n49) In a placebo-controlled study of 72 patients with
advanced AIDS-related illnesses THC was found to reduce nausea,
increase appetite, prevent further weight loss and improve mood
compared to placebo.(n81) Following this study the American Food and
Drug Administration approved the use of THC (dronabinol) for anorexia
associated with AIDS. A question needing further investigation is
whether immunosuppressive effects of cannabinoids may be damaging in
individuals with immune systems already damaged by HIV or
chemotherapy.(n82) THC was found to be ineffective in increasing
appetite or weight gain in anorexia nervosa.(n83)
Cannabinoids in epilepsy
Existing anticonvulsant drugs fail to provide total protection from
fits in a third of epileptic patients and all have adverse effects
which can be severe. Animal work shows that cannabinoids have complex
actions on seizure activity and that they can exert both convulsant
and anticonvulsant effects (see references(n59, n84) for reviews).
Cannabidiol appears to hold promise in human epilepsy since it has an
anticonvulsant spectrum different from standard drugs. It is virtually
devoid of psychoactivity since it does not react with cannabinoid
receptors.(n85)
There have been three controlled trials of cannabidiol in epileptic
patients. Cunha et al.(n86) found that cannabidiol (200-300 mg/day
orally), when added to standard therapy, improved epileptic control in
seven of eight patients while only one of seven patients improved on
placebo. No psychotropic or neurological effects were noted in 16
healthy volunteers who also took cannabidiol. However, Ames &
Cridland(n87) and Trembly & Sherman(n88) found no effect of this dose
of cannabidiol on seizure frequency in a total of 22 epileptic
patients poorly controlled on standard drugs. Added to these equivocal
results are occasional case reports suggesting favourable effects of
smoking cannabis in generalized or complex partial seizures.(n3,
n89-n91) Although the information is sparse, further trials of
cannabidiol as an add-on drug in poorly controlled epilepsy, which is
often severely disabling, would seem to be merited.
Cannabinoids in glaucoma
Glaucoma is the commonest cause of blindness in the western world and
many cases are associated with raised intraocular pressure for which
treatment with miotics, adrenergic agents, beta-blockers or carbonic
anhydrase inhibitors is not always satisfactory. Several
investigations have shown that oral or smoked cannabis or THC, THC eye
drops and some other psychoactive cannabinoids (but not the
non-psychoactive cannabidiol) can reduce intraocular pressure in
normal human subjects.(n92-n96) However, there is scanty information
on the effects of cannabinoids in patients with glaucoma. Only two
double-blind trials have been reported, both short-term. Merritt et
al.(n97) studied 18 patients with glaucoma who received THC (2%) by
smoking. There was a significant fall in intraocular pressure but the
side effects of hypotension, palpitations and psychotropic effects
occurred with such frequency as to rule out routine use with this form
of administration. In a later study,(n98) eight patients with glaucoma
and vascular hypertension received THC in eye drops to one eye only.
There was a decrease in intraocular pressure in both eyes, suggesting
that the effect was due to systemic absorption. In an open study of
smoked or oral THC, seven of 11 patients with glaucoma responded with
a significant drop in intraocular pressure.(n93) Remaining anecdotal
reports include two patients with glaucoma who obtained symptomatic
relief and lowering of intraocular pressure from smoked or orally
ingested cannabis after standard pharmacotherapy had failed.(n3)
Although the evidence shows that cannabinoids can lower intraocular
pressure in some patients with glaucoma, there are disadvantages to
such use. First, tolerance develops within days in normal subjects and
cessation of use is accompanied by a rebound in intraocular pressure
to above baseline levels.(n96, n99) Secondly, although topical
administration is desirable, it is difficult to prepare suitable
preparations of cannabinoids since they are extremely lipid soluble
and water insoluble. Topical administration of 1% THC in mineral oil
had no significant effect on intraocular pressure in normal
subjects.(n100, n101) The available evidence indicates that the effect
of cannabinoids on intraocular pressure in man is due to systemic
actions.(n102) Thirdly, all the cannabinoids which have been shown to
lower intraocular pressure in man have psychoactive and cardiovascular
effects. Finally, cannabinoids themselves may produce undesirable
ocular effects in man, including photophobia, conjunctival hyperaemia,
decreased lacrimation, corneal ulceration, conjunctivitis, keratitis
and changes in pupil size.(n102) Thus, the utility of cannabinoids in
glaucoma is doubtful at present,(n103) although some synthetic and
semisynthetic cannabinoids have been promising in preclinical
studies.(n102, n104)
Cannabinoids in asthma
Acute doses of cannabis exert a bronchodilator action on the small
airways(n105) by a mechanism that appears to be different from that of
betaadrenoceptor agonists and other bronchodilators used at present
for asthma.(n106) Concern over risks of long-term use of potent
betaadrenoceptor stimulants has renewed interest in earlier
studies,(n107, n110) suggesting a possible benefit of cannabinoids in
asthma. Such studies have been limited to acute administration in a
small number of asthmatic patients and a few normal volunteers.
Tashkin et al.(n107) compared the effects of smoked cannabis
containing 2% THC, oral THC (15mg) and inhaled isoprenaline (0.5%) in
14 asthmatic subjects. Both cannabis and THC produced
bronchodilatation nearly equivalent to isoprenaline and smoked
cannabis also reversed experimentally induced bronchoconstriction in
three of the subjects. Similarly, smoked THC (0.9% and 1.9%) produced
bronchodilatation lasting several hours in 17 asthmatic subjects
(109), and an aerosol containing 200 Mu g THC produced equivalent
bronchodilator effects to a salbutamol aerosol (100 Mu g) in 10
asthmatic subjects.(n110) In all these studies, effective doses of
cannabinoids produced adverse effects including psychological
disturbances and tachycardia. Furthermore, Tashkin et al.(n108) found
that a THC aerosol caused moderate to severe bronchoconstriction,
coughing and chest pain or discomfort in two of five asthmatics and
three of 11 normal volunteers. These authors concluded that the
irritant effect of THC on the airways make it unsuitable for
therapeutic use.
Some studies reviewed by Graham(n106) and Archer et al.(n111) have
shown that Delta[sup 8]-THC has bronchodilator actions with little
cardiovascular or psychological effects and that cannabidiol can
reduce the adverse effects of THC without affecting the bronchodilator
action, although neither cannabidiol nor nabilone have bronchodilator
effects.
Thus, the present status of cannabinoids in asthma is doubtful. In
particular, a suitable form of administration needs to be developed,
possibly a metered dose inhaler.(n106) There have been no studies of
long-term use and it is not clear whether tolerance to the
bronchodilator effect would develop. However, combinations of
cannabinoids with standard bronchodilators may have a possible use in
selected patients and there may be a potential for developing
synthetic cannabinoids with selective bronchodilator effects.
Other potential uses
A possible use of cannabinoids as antihypertensire agents is suggested
by the observation that they cause postural hypotension. However,
tolerance to this effect develops rapidly and, since they would have
to be used long-term, their hypotensive properties are unlikely to be
of therapeutic value.(n112)
A variety of uses for the psychotropic effects of cannabinoids have
also been suggested. For example, controlled studies have shown
anxiolytic effects with nabilone,(n113, n114) hypnotic actions with
cannabidiol,(n115) and antidepressant effects of THC in cancer
patients,(n116) although there have been no formal comparisons with
standard drugs. A role in opioid withdrawal has also been suggested
since animal work and a few anecdotal reports in man suggest that
cannabiholds can inhibit some opioid withdrawal effects by a
non-opioid mechanism.(n117)
The development of novel synthetic opioids may yet open new vistas:
one such compound, (+)-HU-210, is an antagonist of NMDA
(N-methyl-D-aspartate) receptors and may protect against excitotoxic
effects in strokes, head injuries and neurodegenerative
disorders.(n59)
Advantages and disadvantages of clinical use of cannabinoids
The major advantage of cannabinoids is that they are extremely
non-toxic: no deaths have resulted from their use and their
side-effects profile compares favourably with that of many drugs used
for conditions in which cannabinoids have a therapeutic potential.
However, for all their promise, there may be limitations to the
clinical use of cannabinoids.
Sedation
The most common adverse effect in clinical trials of cannabinoids is
sedation (incidence 50-100%) with drowsiness, confusion, poor memory
and general cognitive and psychomotor impairment. These effects may be
of importance if cannabiholds are used long-term for chronic
conditions and have implications for activities such as car driving
and operating machinery, especially since they are additive with other
sedative drugs.(n118) Furthermore, elimination of cannabinoids is
extremely slow; they are concentrated in body fat and complete
elimination of a single dose may take up to 30 days.(n119) Clearly,
repeated dosage results in accumulation and effects on cognitive and
psychomotor performance may be long-lasting.(n82)
Psychological effects
The second most common effects in clinical trials are psychological,
including euphoria, dysphoria, anxiety, depersonalization,
hallucinations, paranoia and depression. Certain individuals may be
particularly sensitive to these effects, and cannabis can aggravate
psychosis in patients with schizophrenia, lead to loss of control with
anti-psychotic drugs and possibly precipitate schizophrenia in
vulnerable subjects.(n120, n121)
Physical effects
Also common are physical side-effects of cannabinoids. These include
dry mouth, ataxia (incidence over 50%), general inco-ordination,
muscle weakness and tremor. Tachycardia and hypotension may make
cannabinoids unsuitable for patients with cardiovascular disease.
Endocrine effects may preclude their use in children and in pregnancy,
and immunosuppressant effects may be of importance in immunocompromised individuals.(n105, n117)
Tolerance, dependence, withdrawal effects
Tolerance develops rapidly, although incompletely and unevenly, to
many of the effects of cannabis including those on mood, heart rate,
blood pressure, intraocular pressure and psychomotor
performance.(n99)
Such tolerance may be an advantage in overcoming unwanted effects but
a disadvantage if it develops to therapeutic effects. In recreational
settings cannabis can cause dependence and an abstinence syndrome on
withdrawal. However, by analogy with opioids used in pain relief(n122)
abuse or addiction are unlikely to become problems with prescribed
dosage of cannabinoids in therapeutic settings. Nevertheless,
precautions may be necessary to prevent prescribed cannabinoids being
subverted like benzodiazepines, other hypnotics and amphetamines) into
illicit "street" use.
Withdrawal effects may be clinically undesirable. These can include
psychological effects (anxiety, insomnia) and also physical effects
such as a rebound rise in intraocular pressure to above baseline
levels, nausea, diarrhoea and other physical symptoms.(n99) For this
reason it would be advisable to taper dosage gradually on
discontinuation after regular use of cannabinoids for more than a few
weeks.
Modes of administration
Optimal modes of administration of cannabinoids have yet to be
devised. Most clinical studies have involved the use of oral THC or
nabilone, but absorption by this route is variable, slow and
prolonged.(n119) Absorption of inhaled THC is rapid and almost
complete but suitable aerosols of cannabinoids are not generally
available. Individuals who have self-administered cannabis for medical
purposes often claim that smoked herbal cannabis gives the best
results, taking effect within minutes and allowing them to judge the
dosage required for symptom control.(n3) However, this method cannot
be recommended for long-term use since the smoke from herbal cannabis
contains the same harmful constituents as tobacco smoke (apart from
nicotine) and exposure to bronchial irritants, carcinogens and carbon
monoxide is greater than from a tobacco cigarette.(n123, n124)
Furthermore, even in herbal preparations standardized for THC content,
concentrations of other cannabinoids may be variable. Rectal
administration allows rapid and efficient absorption(n125) but may not
be acceptable to many patients. Eye drops, buccal preparations and
skin patches still require development. Finally, optimal dosage
regimens, cannabinoid combinations and co-administration with standard
drugs require further research.
Drug accumulation
After systemic absorption, the elimination of cannabinoids is
extremely slow. The plasma elimination half-life of THC is about 56
hours in occasional cannabis users and about 28 hours in chronic users
because of an increased rate of metabolism.(n126) However, because
cannabinoids are highly fat soluble they are sequestered in fatty
tissues, from which they are only slowly released. Thus the tissue
half-life of THC is about 7 days while complete elimination of a
single dose may take up to 30 days.(n119) Because of the sequestration
in fat, high concentrations of cannabinoids can accumulate with
repeated or chronic use and continue to reach the brain (which has a
high lipid content), possibly exerting long-lasting effects.
Accumulation of cannabinoids might theoretically be a problem if they
are used daily for chronic conditions such as multiple sclerosis, but
there have been no studies on the effects of long-term regular
clinical use of cannabinoids.
Cannabinoids are metabolized in the liver. A major pharmacologically
active metabolite is 11-hydroxy-THC; more than 20 other metabolites
are known, some of which may be psychoactive. 11-Hydroxy-THC and many
of the other metabolites have plasma elimination half-lives of the
order of 50 hours. Further metabolism produces inactive metabolites,
of which 15-30% are excreted in the urine. Both active and inactive
metabolites are also excreted into the intestine and bile and about
15% of them are reabsorbed, prolonging the actions of cannabis, while
35-65% are finally eliminated in the faeces.(n119)
Nabilone is more rapidly eliminated than THC.(n127) The plasma
half-life of the parent compound is estimated to be approximately 2
hours. It is extensively metabolized and single oral dose studies in
man using radioactively labelled nabilone showed that 84% of the dose
was recovered in the faeces (60%) and urine (24%) after 7 days. Tissue
accumulation of nabilone or its metabolites must clearly occur if the
drug is given daily, but in clinical studies of patients taking oral
nabilone 3 mg daily for 21-28 days, there was no evidence of
drug-related cumulative toxicity. A dose of 1 mg nabilone on alternate
days was sufficient to relieve symptoms in multiple sclerosis(n64)
(Fig. 2)
Conclusions
The place of cannabinoids in modern medicine remains to be evaluated
and the results of clinical and pharmaceutical research will be
awaited with interest. Recommendations for such research have been
suggested under each indication discussed in this review. It seems
that cannabinoids are unlikely to constitute a cure for any illness,
but on present evidence it is possible that they could be valuable for
symptom control in a variety of conditions for which available drugs
are not fully satisfactory. They are most likely to find a place as
adjuvants to standard agents, and it is possible that the development
of novel synthetic agents with more specific actions and fewer
side-effects will extend their therapeutic range. Meanwhile, several
authorities(n5, n6, n128) have argued for enhanced access to
cannabinoids in clinical practice and the British Medical Association
report(n5) concludes: "While research is underway, police, the courts
and other prosecuting authorities should be aware of the medicinal
reasons for the unlawful use of cannabis by those suffering from
certain medical conditions for whom other drugs have proved
ineffective."
Correspondence to: C.H. Ashton, Department of Psychiatry, University
of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne
NE1 4LP, UK, Tel: 0191 222 6000, ext. 6978, Fax: 0191 227 5108.
Received for publication 11th October 1998. Accepted 21st December
1998.
Table 1. Double-blind clinical studies of cannabis or cannabinoids
involving 10 or more patients
Legend for Chart:
A - Subjects
A
Anti-emetic effects in patients on cancer chemotherapy
(studies since 1985)
Lane et al.(n42)
62 patients on various cancer chemotherapy
THC (dronabinol) 10 mg qds
PCP 10 mg qds
Both drugs together
No nausea or vomiting: 51% for THC,
83% for PCP; PCP and THC combined
better than either alone
Niiranan & Mattson(n31)
24 patients on various cancer chemotherapy
Nabilone 2 mg 6-hourly
BIOMEDICAL BENEFITS OF CANNABINOIDS?
Subject(s): CANNABIS -- Therapeutic use; CANNABINOIDS
Source: Addiction Biology, Apr99, Vol. 4 Issue 2, p111, 16p, 1
diagram, 1 graph
Author(s): Ashton, C. H.
Abstract: Reviews the clinical trials which have been carried out
with cannabinoids including tetrahydrocannabinol (THL) and synthetic
cannabinoids. Advantages and adverse effects of cannabinoids in
clinical use; Medicinal uses of cannabis and cannabinoids;
Double-blind clinical studies of cannabis or cannabinoids involving
ten patients.
BIOMEDICAL BENEFITS OF CANNABINOIDS?
Two types have been identified: CB[sub 1] receptors in the brain and
peripheral nerves(n9, n10) and CB[sub 2] receptors in macrophages in
the spleen and immune cells in other tissues.(n11) Both CB[sub 1] and
C - Drug and dose
D - Results
B
C
D
PCP 15 mg 6-hourly
Nabilone significantly better than PCP
for nausea and vomiting, and preferred
by most patients though more side
effects
Niederle et al.(n32)
20 patients on cisplatin
Nabilone 2 mg 6-hourly
Alizapride 150g tds
Nabilone more effective than alizapride
though more side effects
Pomeroy et al.(n33)
38 patients on various cancer chemotherapy
Nabilone 1 mg 6-hourly
Domperidone 20 mg 6-hourly
Nabilone superior to domperidone
Dalzell et al.(n18)
23 children on various cancer chemotherapy
Nabilone 0.5-1 mg bd or tds.
Domperidone 5-15 mg tds.
Nabilone superior to domperidone
Two-thirds of children preferred
nabilone
Chan et al.(n34)
30 children on various cancer chemotherapy
Nabilone
PCP
Nabilone superior to PCP
Antispastic effects in multiple sclerosis (MS)
Ungerleider et al.(n63)
13 patients with MS
Oral THC 2.5-15 mg once or
twice daily for 5 days, or
placebo
Subjective improvement in spasticity at
doses of 7.5 mg or above, but no change
in objective measures of weakness,
spasticity, coordination, gait or reflexes.
Side effects in 12 patients on THC and
5 patients on placebo
Greenberg et al.(n65)
10 patients with MS
10 normal controls
Smoking cannabis (1.54%
THC)single dose; or placebo
Cannabis impaired posture and balance
in all subjects, causing greater
impairment in MS patients. No other
objective changes but subjective
improvement with cannabis in some
patients. "High" experienced with
cannabis
Analgesic effects
Noyes et al.(n74)
10 patients with cancer pain
Oral THC 5, 10, 15, 20 mg,
or placebo
Significant pain relief with 15 and 20 mg
THC compared to placebo. Sedation
common with THC
Noyes et al.(n75)
36 patients with cancer pain
Oral THC 10 and 20mg.
Oral codeine 60 and 120 mg,
or placebo
THC 20 mg and codeine 120 mg gave
equivalent and significant pain relief
compared to placebo. THC caused
sedation
Jain et al.(n76)
56 patients with postoperative pain
IM levonantradol 1.5-3 mg or
placebo
Significant pain relief with both doses of
levonantradol compared with placebo
Drowsiness common with levonantradol
Raft et al.(n78)
10 patients undergoing dental extractions
IV THC 0.22 mg/kg and
0.44 mg/kg
IV diazepam 0.157 mg/kg or
placebo
No analgesic effects of THC detected.
THC rated as least effective, diazepam
most effective
Effects in anorexia
Gross et al.(n83)
11 patients with anorexia nervosa
Oral THC 7.5-30 mg/day
Diazepam 3-15 mg/day for 2
weeks, or placebo
No significant difference in weight gain
between THC and diazepam. Dysphoria
with THC
Beal et al.(n81)
72 patients with AIDS-related illness
THC 2.5 mg bd or placebo
for 6 weeks
Significant reduction in nausea and
weight loss, increased appetite and
improved mood with THC compared to
placebo
Anticonvulsant effects
Cunha et al.(n86)
15 patients with poorly controlled
generalised epilepsy 16 healthy volunteers
Oral cannabidiol 200-300 mg/
day added to standard therapy
in patients
Oral cannabidiol 3 mg/kg/day
in controls, or placebo in both
groups.
Treatment for 4-5 months
Cannabidiol improved control in 7 of 8
patients; 1 of 7 patients improved on
placebo. Sedation in 4 patients on
cannabidiol.
No adverse effects in controls
Ames & Cridland(n87)
12 epileptic patients poorly controlled
on standard drugs
Oral cannabidiol 200-300 mg/
day for 4 weeks or placebo
No significant effect on seizure
frequency
Trembly & Sherman(n88)
10 patients with poorly controlled
epilepsy, mixed types
Oral cannabidiol 300 mg/day
added to standard drugs for 6
months or placebo
No effect on seizure pattern or
frequency
Effects on glaucoma
Merritt et al.(n97)
18 patients with glaucoma
Smoking THC 2%, or placebo
Reduction in intraocular pressure with
THC but palpitations, hypotension and
psychotropic effects
Bronchodilator effects in asthma
Tashkin et al.(n108)
14 asthmatic subjects
Smoked THC 2%, oral THC
15 mg, isoprenaline 0.5%, or
placebo.
Bronchodilation with THC nearly
equivalent to isoprenaline
Smoked THC reversed experimentally
induced bronchospasm in 3 patients
Vachon et al.(n109)
17 asthmatic subjects
Smoked THC 0.9% and 1.9%
(single-blind)
THC produced bronchodilation lasting
several hours, tachycardia at higher dose
Williams et al.(n110)
10 asthmatic subjects
THC 200 Mu g in metered dose
inhaler
Salbutamol aerosol 100 Mu g, or
placebo
THC and salbutamol improved
ventilation, equivalent at 1 hour
PCP = prochlorperazine.
Table 2. Properties of some natural and synthetic cannabinoids
Legend for Chart:
A - Plant cannabinoids
A
B
Delta[sup 9]-tetrahydrocannabinol (Delta[sup 9]-THC)
(available in synthetic form as dronabinol)
Main psychoactive cannabinoid in Cannabis
sativa. Largely responsible for psychological
and physical effects
Delta[sup 8]-tetrahydrocannabinol (Delta[sup 8]-THC)
(available in synthetic form)
Slightly less potent than Delta[sup 9]-THC.
Appears to have fewer psychotropic effects
Cannabinol
Less potent than Delta[sup 9]-THC
Cannabidiol
Does not interact with cannabinoid receptors.
No psychotropic effects but may have anticonvulsant
and analgesic properties; may attenuate
psychotropic effects of Delta[sup 9]-THC
Endogenous cannabinoids
Anandamide (arachidonyl ethanolamide), one of a
family of similar endogenous cannabinoids
Interacts with cannabinoid receptors and mimics
actions of Delta[sup 9]-THC in animals. Has
not been tested in man
Synthetic cannabinoids
Nabilone
Similar properties to Delta[sup 9]-THC but
more potent. Higher incidence of dysphoria but
less euphoria and lower abuse potential
Levonantradol
Similar properties to Delta[sup 9]-THC but
more potent analgesic effects. High incidence
of dysphoria and sedation
DIAGRAMS: Figure 1. Chemical structure of main cannabinoids in
Cannabis sativa.
GRAPH: Figure 2. Symptoms while receiving nabilone or placebo in a
patient with multiple sclerosis (with permission form Martyn et
al.(n39)
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~~~~~~~~
By C. H. Ashton, Department of Psychiatry, University of Newcastle
upon Tyne, UK