Abstract
1990 marked the discovery of receptors, which could
bind cannabis' active ingredient (THC) as if our body
had been made to use cannabinoids. In 1992 researchers
found that our body too produces a substance called
"endocannabinoid" (anandamide) that can
bind the same natural cannabinoid receptors, like
the endorphins produced by our body, which act like
morphine and heroine (diacetylmorphine) introduced
from the outside. Many scientific works highlight
the efficacy of cannabinoid treatment in various clinical
conditions:
1) treatment of nausea and vomiting in oncological
patients who undergo chemotherapy;
2) stimulation of the appetite in patients suffering
from AIDS who present the wasting syndrome;
3) treatment of spasticity in multiple sclerosis and
bone marrow lesions (controlled clinical trials are
still in progress); 4) treatment of chronic pain in
various diseases. Their use has promising potential
in some special forms of chronic pain (pain resulting
from muscle spasticity, neuropathic pain) that are
poorly sensitive to traditional pain killers. In animals
cannabinoids have shown analgesic properties, which
can be compared to the so-called "minor opiates"
and present a synergic action; to be precise they
increase the efficacy of morphine in pain treatment,
thus reducing both the dosage and hence the side effects
of morphine itself. There is considerable data on
animals but little data on man, as yet. In Italy a
multicentre study focused on oncological patients
is starting, involving Rome (Umberto I General Hospital
Administration, "La Sapienza" University),
Turin (Molinette San Giovanni Battista Hospital Administration)
and the Beth Israel Medical Center, New York). It
is a randomised multicentre study versus placebo,
whose duration will be 4 weeks. Its goal is to evaluate
the analgesic efficacy of THC combined with morphine
in oncological patients with average to serious pain.
The study also proposes to prove the improvement of
the quality of life gauged through emotional parameters
and the reduction of nausea and neoplastic cachexia.
Patients will be treated either with morphine sulphate
or with morphine sulphate and THC:CBD (a complete
extract of the Cannabis sativa plant administered
as an oral spray (Sativex®). One group of patients
will be treated only with morphine sulphate, another
with morphine sulphate + Sativex® and the last
one with morphine sulphate + placebo.
In Italy it has been very hard to use cannabis derivatives
for medical purposes because there are neither legal
sources of supplies nor does the Italian market have
products based on cannabis and its derivatives, while
these products can be legally imported from abroad
- especially from other EU countries - naturally with
a medical prescription (Ministerial Decree dated 11/02/1997,
art. 2). However the procedure is very complex and
comprises many stages: the Import License Application
drafted by the treating physician and the patient's
Informed Consent Form must be presented through a
hospital pharmacy or another pharmacy belonging to
the territory's competent Local Health Administration
to the Ministry of Health - Central Narcotics Office,
which must issue the authorisation. The new law does
NOT envisage the therapeutic use of natural or synthetic
cannabis derivatives. Many chemical substances, such
as cannabinol, cannabidiol and THC or delta-9-tetrahydrocannabinol
(delta-9-THC) have been found in Cannabis sativa,
a herbaceous perennial, which belongs to the Cannabinaceae
family. THC is cannabis' best known active component
and can be considered as the father of the phytocannabinoid
family. This compound acts on the central nervous
system (CNS) causing euphoria, distorted perception
of time, altered hearing and visual perceptions and
sedation (all such actions are exploited in the recreational
use of drugs). Besides it has other psychoactive actions,
which can be used for therapeutic purposes: it relieves
pain, prevents nausea and kinetosis, stimulates the
appetite, reduces intraocular pressure and tremor.
It also acts on many peripheral organs, such as lungs
(alveolar dilation), heart (tachycardia), vascular
system (vasodilation) and immune system (inhibition
of immune functions). Studies on the action of delta-9-THC
isolated by Gaoni and Mechoulam in 1964 led to the
theory that exogenous cannabinoids had to act through
a specific cell receptor system. In 1990 Matsuda and
colleagues found in the rat brain a specific receptor
coupled with a G protein and able to both bind THC
and inhibit adenylate cyclase. Recalling at this point
the endogenous opioid system, it was natural to seek
the endogenous substance that could bind and activate
the receptor. And in 1992 Devane and colleagues isolated
the first endocannabinoid and called it anandamide,
which means "eternal beatitude" in Sanskrit.
In the years that followed other endocannabinoids
were discovered: 2-arachidonoyl-glycerol and 2-arachidonoyl-glyceril,
endogenous compounds that act on the same receptors,
which bind exogenous THC and lead to the typical effects
of the active compounds of cannabis. Studies on the
endocannabinoid system enabled to locate the main
sites where cannabinoid receptors are present; two
different types of receptors called CB1, present both
in the central nervous system (CNS) and in the peripheral
nervous system, and CB2, present especially in immune
cells and in the autonomic system, were recognised.
Cannabinoids interact with a wide spectrum of neurotransmitters
and neuromodulators, such as acetylcholine, dopamine,
gamma aminobutyric acid (GABA), histamine, serotonin,
glutammate, noradrenalin, prostaglandin and endogenous
opiods. Some pharmacological effects can be explained
on the basis of interactions with these receptor systems,
such as, for instance, the effect on spasticity through
interactions with GABA, glutamergic and dopaminergic
systems. The distribution of cannabinoid receptors
in the brain suggests a physiological role in the
control of pain, movement and perception and in regulating
emotional conditions; this role is similar and complementary
to the one exercised by endorphins both in the central
and peripheral system and in learning and memory processes
and, it has paved the way to understand their therapeutic
potential. The main functional areas with the highest
concentration of CB receptors are: cortex cerebri
(cognitive and learning processes), hippocampus (memory),
basal ganglia and cerebellum (control of locomotor
activities), grey matter around the Sylvian acqueduct
and the spinal cord's posterior horn (pain modulation),
hypothalamic centres (appetite regulation), besides
organs belonging to the immune system (peripheral
leukocytes, thymus, spleen, pancreas).
Possible Clinical Usage of Cannabis
Compounds based on either natural or synthetic cannabis
are administered in various diseases, but there is
currently no basic clinical data concerning their
real efficacy in all the diseases proposed. We can
in fact distinguish diseases in which: A) the effect
has been scientifically proved: treatment of nausea
and vomiting caused by chemotherapy and stimulation
of the appetite in patients wìth AIDS-related
wasting syndrome; B) the effect has been relatively
confirmed: THC's effect on spasticity in patients
suffering from multiple sclerosis or spinal lesions,
chronic pain and Tourette's syndrome is doubtful,
just as it is doubtful in movement disorders (dystonia
and iatrogenic dyskinesia), asthma and glaucoma; C)
the effect has not been entirely confirmed: beneficial
effects have been reported in allergies, inflammatory
diseases, epilepsy, non responsive hiccups, depression,
bipolar disorders, anxiety, addiction to opioids and
alcohol and, behavioural disorders in patients with
Alzheimer's disease; D) studies are in progress: possible
therapeutic use in hypoxic damage to the CNS, in autoimmune
diseases, as prevention of neoplastic diseases and
to stimulate appetite in patients with AIDS-related
wasting syndrome: it is known that the maintenance
of an appropriate calorie intake and body weight is
critically important towards the prognosis of patients
infected with HIV. Signs of malnutrition may appear
when an appropriate intake of food cannot be guaranteed
due to the presence of infections in the digestive
system. A drop in body weight beyond a certain threshold
causes the picture of the so-called wasting syndrome,
which is often associated with an inauspicious prognosis.
In patients with wasting syndrome unsatisfactory results
have been obtained with most appetite stimulant drugs
studied. Megestrol acetate (Megace ®), a progesterone
derivative, administered in high doses (320-640 mg/day)
produced some results in terms of weight increase,
but this was mostly due to an increase in body fat.
Cannabis derivatives capacity to stimulate the appetite
has been long known and is an experience that is common
to many who make a 'recreational' use of it. Some
anecdotic evidence suggested the possibility of using
this property for therapeutic purposes in HIV positive
patients (Grinspoon, 1993). Studies conducted on healthy
volunteers have confirmed that marijuana smoke increases
appetite and the intake of food, thus increasing body
weight (Foltin, 1988). Recently a group of Italian
researchers proved that the endogenous cannabinoid
system plays a central role in regulating the intake
of food (Di Marzo, 2001) and later various controlled
clinical studies confirmed the appetite stimulating
efficacy of a synthetic cannabinoid - dronabinol -
in HIV positive patients. The FDA has authorised its
use as an "appetite stimulant in patients with
AIDS-related weight loss" since 1992; the drug
was later registered, with this specific indication,
in some European countries too.
The problem of possible negative interactions between
cannabis and the immune system and of possible harmful
interactions between antiviral drugs and cannabis
derivatives in these patients have been considered
since protease inhibitors and THC make use of the
same metabolic routes in the liver. The first study
involved 67 patients treated with protease inhibitors.
One study showed that there are no statistically significant
differences concerning the progress of virus levels
in the blood between the three groups which respectively
took cannabis by inhalation, dronabinol and placebo
(Abrams, 2001); an average gain of 2.2 kg in body
weight was observed in patients treated with cannabis
derivatives (either natural or synthetic) against
0.6 kg in those treated with placebo. The result was
that cannabinoids, both natural and synthetic, had
no negative impact on antiviral treatment nelfinavir
and indinavir in patients with AIDS and besides stimulating
the appetite, they are also effective in reducing
nausea and other side effects caused by antiviral
drugs. (Kosel, 2002).
The British Medical Association has defined cannabis
derivatives as a useful tool in the treatment of HIV
infections, saying that further detailed studies must
focus on them. (Robson, 1998)
Treatment of Nausea and Vomiting in Patients
Under Chemotherapy
Every year in Italy ca 300 thousand patients suffering
from a tumour undergo chemotherapy treatment. Such
treatments are at times very debilitating and cause
many side effects. Many commonly used chemotherapic
drugs frequently cause nausea and vomiting. And this
is an important problem because the real complication
is that these patients are often already very debilitated
and the failure to maintain a regular intake of food
causes them to decline further. Antiemetic drugs can
in turn have side effects on the central nervous system
too, especially sedation. The first evidence of cannabis
smoke's positive action in controlling nausea and
vomiting caused by chemotherapy date back to the '70s.
The antiemetic efficacy of delta-9-tetrahydrocannabinol
(THC) was confirmed by many studies controlled both
with placebo and with traditional antiemetic drugs.
These studies found that cannabinoids were more effective
than traditional treatment. A review recently published
in the British Medical Journal (Tramèr, 2001)
selected thirty works that meet scientific validity
criteria and involve ca 1,400 patients. All these
studies found that the antiemetic efficacy of cannabinoids
was higher than that of traditional drugs (prochlorperazine,
metoclopramide, chlorpromazine, thiethylperazine,
haloperidol, domperidone and alizapride). Both natural
and synthetic cannabis derivatives stimulate CB1 receptors
in brain areas assigned to control vomiting (Darmani,
2001) and, it has been recently suggested that the
endogenous cannabinoid system plays a leading role
in modulating this function.
Cannabis and Multiple Sclerosis.
Multiple sclerosis (MS) is a disease that strikes
ca 3,000,000 people in the world, 400,000 in Europe
and 50,000 in Italy. It is the neurological disease,
which causes the highest number of disabled. Every
year there are 1,800 new cases in Italy - one every
4 hours, one on 1,200 inhabitants suffers from the
disease. 60% of patients with MS complains of pain.
In individuals who suffer from the disease, immune
system cells destroy the myelinic sheath, which protects
the cells of brain and bone marrow nerves, thus causing
progress and clinical pictures that greatly vary.
It causes many symptoms, which are often chronic,
numbering muscle spasticity, twitching, pain, tremor
and bladder problems. Much evidence has backed the
opinion that the psychoactive elements present in
Cannabis sativa can act positively on the various
symptoms associated with the disease, especially on
spasticity, pain, bladder disorders and sleep alterations;
these disorders are especially present in the disease's
progressive phase and their management is difficult
even today. Many articles have been published on the
topic, especially in prestigious reviews: 35 studies
on animal and biological models (bibliographical search
with the keyword cannabis, experimental research and
laboratory research), 17 articles on experimental
protocols on man (phase 2 and 3 clinical trials),
and 44 articles that review the subject. In 2003 the
Lancet published an extensive multicentre, randomised,
placebo-controlled study for symptomatic treatment
conducted on 630 patients with MS (Zajicek JP, Lancet
2003). The study did not highlight any significant
effects of cannabis (either cannabis extract or THC)
used by patients to treat muscle spasticity for a
period of 15 weeks. However most patients who took
the drug found that it reduced their spastic symptoms,
also improving deambulation and pain. There is no
clear explanation for the difference found between
objective and subjective results on spasticity; the
research group suggested that this probably mirrored
a reduced expression of spasticity rather than an
effect on muscle rigidity per se. In 2005 the same
author published data related to the effects of treatment
on 502 patients who had decided to continue experimental
treatment for 12 months, also showing a limited but
positive long term effect on certain aspects of disablement
and especially on spasticity. (Zajicek JP, JNNP 2005)
Fig. 1
Freeman RM (Int Urogynecol J Pelvic Floor Dysfunct
2006) recently published data concerning a possible
beneficial effect of cannabis on bladder disorders
in patients with MS: the three groups under different
treatment (cannabis extract, THC or placebo) showed
a significant reduction in the bladder disorder: 38%
in the group treated with cannabis extract, 33% in
the THC group and 18% in the placebo group. Brady
CM (Mult Scler 2004) performed an open study on the
possible effects of cannabis on bladder disorders
in patients suffering from MS. He studied 15 patients
treated for eight weeks with THC: CBD (Sativex®)
and for another eight weeks only with THC. The data
collected showed a significant improvement in micturition
urgency, nycturia and in the number of episodes of
incontinence. The subjective perception of pain, spasticity
and quality of sleep also improved significantly.
Recently Rog DJ (Neurology 2005) administered THC:CBD
for five weeks (Sativex®) to 66 patients with
MS and central pain that was non responsive to treatment
in a randomised, double-blind, placebo-controlled
study conducted in parallel groups. The active treatment
was well tolerated and really effective in reducing
pain and sleep disorders. Some studies instead showed
effects on central neuropathic pain. In a cross-over
randomised double-blind placebo-controlled study Svendsen
KB (BMJ 2004) administered dronabinol orally for three
weeks and placebo for another three weeks after a
two week interval between the two treatment phases.
The 24 patients treated with the active drugs showed
a significant 21% reduction in the pain experienced,
compared to the one felt at the start of the study,
besides relevant subjective relief. Hence literature
numbers many publications, which suggest cannabis
and its derivatives' therapeutic effect. This data
calls attention to the need for more accurate extensive
studies to define the efficacy, dosage, therapeutic
indications and undesired effects, to establish which
cannabis extract components are more effective and
whether the individual components are more or less
active than the raw extract in which all are present.
In Italy Professors C. Pozzilli and M. Inghilleri
are completing an important study on the effects of
Sativex in MS.
Analgesic Action in Oncological Pain
Cannabinoids have analgesic properties that are comparable
to those of the so-called "minor opiates".
They enhance the efficacy of morphine in pain treatment
and their use holds promising potential for the treatment
of oncological pain (3,4). Morphine is an essential
drug in the treatment of acute oncological pain, but
its prolonged use also causes rather relevant undesired
side effects: constipation, respiratory depression
and nausea, besides tolerance and physical addiction.
Cannabinoids' analgesic action in animal models is
long-term; their strength resembles opiods and they
are well tolerated. In fact undesired side effects
are usually not serious. In acute patients they are
psychoactive (dysphoria, slowed thought processes,
altered space-time perception, dizziness, anxiousness,
panic attacks and altered motor function), while in
chronic patients they number immune system impairment
and addiction in groups with a high risk of tumours
(marijuana smokers). Cannabinoids can inhibit pain
by acting on CB1 or CB2-like receptors at various
levels: in the brain where they regulate synaptic
transmission by preventing the release of the antinociceptive
descending system's neurotransmitter at a spinal level
where the concentration of CB1 cannabinoid receptors
is high in afferent nociceptive pathways (Fig
2).
Besides the activation of CB1-like and CB2-like
receptors regulates the start of pain in the skin,
suggesting that besides a spinal and supraspinal action,
cannabinoids participate in reducing pain signals
in the tissue (Fig 3).
The analgesic efficacy of cannabinoids is stronger
in neuropathic pain than in nociceptive pain, in chronic
pain than in acute pain and their action is synergic
with opioids. Extensive experimental evidence shows
that the combined use of morphine and cannabinoids
can offer advantages in the treatment of acute oncological
pain, especially pain that is non responsive to opioids.
The morphine-THC interaction is synergic; to be precise
the effect produced is stronger than the sum of the
effects produced by the single drugs (Cichewitz et
al 2004) (Fig 4).
The analgesic effect of either morphine or codeine
is enhanced by their combination with THC at doses
that are per se ineffective. THC also enhances the
analgesic effect of other? opiates (Cichewitz et al
1999). Data reveals that morphine too enhances the
analgesic effect of THC. Both naloxone and the compound
SR141716A (CB1 cannabinoid receptor antagonist) block
the combination's analgesic effect. The mutual capacity
to release either endocannabinoids or endogenous opioids
could justify the two systems' enhanced action. The
promising results obtained in laboratory animals both
after acute and chronic treatment are a promising
approach for pain treatment. In fact the synergism
between morphine and THC enables to combine low doses
of both drugs, thus reducing their side effects and
slowing the development of tolerance to morphine.
Besides the use of carefully titred combinations of
opioids and cannabinods could improve the quality
of oncological pain treatment, because besides increasing
the analgesic effect's strength, it can also reduce
emesis and anorexia symptoms. In fact there are many
problems, which are hard to solve in palliative treatment:
anorexia, weight loss cachexia, nausea and vomiting,
moderate to acute pain, anxiousness and depression
and, cannabinoids are currently the only drugs that
are effective in reducing most of these symptoms.
Besides they involve a single treatment that increases
appetite, reduces nausea and vomiting, improves pain
and the mood and can be a potential and useful tool
in palliative medicine. Fig.5
Concerning side effects resulting from the chronic
use of these substances - doubtless the most relevant
ones are immunological impairment and addiction in
"high risk" groups - it is important to
recall that the life expectation of patients who could
be treated with cannabinoids and morphine is unfortunately
very short: just a few weeks or months. Lastly we
must recall that the effects of cannabis on mood,
sleep and stress are the important aspects that should
be considered in clinical trials. In fact euphoria
is often described as a side effect of cannabinoids.
Is it really an '"unpleasant experience"
for the terminally ill? There is also little data
as yet on the therapeutic efficacy of the morphine-cannabinoid
combination in acute oncological pain in man (Naef
et al 2003)(Gw Webside 2005). Fig. 6
An international multicentre study involving the
Umberto I General Hospital and the La Sapienza University
in Rome (Professors R. Cerbo, C. Cartoni, E. Cortesi,
C. Reale and L. Frati), Molinette San Giovanni Battista
Hospital Administration (Professors A. Mussa and E.
Torta), Beth Israel Medical Center, New York (Prof.
M. Pappagallo) is being organised in Italy. It is
a randomised multicentre study, whose duration will
be 4 weeks (28 days). It will number a population
of 270 patients. Its chief goal will be the assessment
of the analgesic efficacy of THC in adjuvant treatment
with opioids, compared to monotherapy with opioids.
Besides the study will evaluate improvement in the
quality of life (a reduction in disablement, anxious
depressive symptoms and disease-related behaviour
and focus on an increase in appetite) and a reduction
in nausea and vomiting in the various groups. The
study drugs will be THC:CBD (Sativex®) and morphine
sulphate administered orally (20-60 mg).
Legislative Situation Concerning the Use
of Cannabinoids in Medicine
In recent years the pharmaceutical industry has produced
many synthetic cannabinoids, some of which have been
registered for therapeutic use and marketed in various
countries. In particular we must mention dronabinol
(Marinol®), produced by Solvay Pharmaceuticals
Inc. and marketed in Germany, Holland and the USA
and nabilone (Cesamet®), whose pharmacological
properties resemble THC; produced by Cambridge Laboratories
Ltd, UK, it has been marketed in Great Britain, Canada,
Germany, Belgium, Holland, Switzerland, Israel and
South Africa. Both products have been approved to
treat nausea and vomiting in antitumoural chemotherapy
and anorexia in AIDS patients. Dronabinol can also
be found in the European Union as a generic drug (Dronabinol).
Two medicinal specialties based on Cannabis Sativa
inflorescences - Bedrocan® and Bedrobinol®
- have been recently added; they can be found in Dutch
pharmacies from 1 September 2003. The sale of THC:CBD
(Sativex®) has instead been recently approved
in Canada, Great Britain and the USA to treat pain
in patients with MS. Canada is the only country in
the world, which has authorised the use, possession
and cultivation of marijuana for medical purposes
since 2001.
Such practices are regulated by Marijuana Medical
Access Regulations for oncological patients and for
those who suffer from multiple sclerosis, AIDS, epilepsy
and terminal diseases. From 23 October 2004 the government
has authorised the distribution of medical marijuana
through the pharmacy network. Circa 800 Canadian patients
are currently authorised to use and possess marijuana
for medical purposes. In Italy the medical use of
cannabis derivatives is very difficult because there
are no legal sources for supplies and the Italian
market has no products based on cannabis and its derivatives.
Instead these products can be legally imported from
abroad, especially from other EU countries, naturally
with a medical prescription (Ministerial Decree dated
11/02/1997, art. 2 concerning the importation of medicinal
specialities registered abroad). The latest Legal
Decree (March 2006) has included cannabis and its
derivatives in Table I, which numbers all substances
that have no therapeutic use and which hence cannot
be prescribed. The former Minister Storace issued
a decree authorising the use of the old legislation's
regulations for the following 90 days. However the
procedure is very complex and requires the authorisation
of the Ministry of Health - Central Narcotics Office,
the intervention either of the hospital pharmacy or
another pharmacy belonging to the territory's competent
Local Health Administration or the intervention of
a magistrate.
We must stress that due to its complexity, this procedure
has repeatedly proved to be a sort of "obstacle
race", a source of bureaucratic hitches, snags
and delays, which expose patients who resort to it
to considerable inconvenience, often even questioning
the possibility of administering the treatment on
an ongoing basis.
Prof. Rosanna Cerbo
Neurologist and Psychiatrist;
Professor of Neurology, 1st School of Medicine and
Surgery, La Sapienza University, Rome, Italy
