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Cannabinoids in the treatment of rheumatic diseases: Pros and cons

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Medical cannabis is being increasingly used in the treatment of rheumatic diseases because, despite the paucity of evidence regarding its safety and efficacy, a growing number of countries are legalising its use for medical purposes in response to social pressure. Cannabinoids may be useful in the management of rheumatic disorders for two broad reasons: their anti-inflammatory and immunomodulatory activity, and their effects on pain and associated symptoms. It is interesting to note that, although a wide range of medications are available for the treatment of inflammation, including an ever-lengthening list of biological medications, the same is not true of the treatment of chronic pain, a cardinal symptom of many rheumatological disorders. The publication of systematic reviews (SR) concerning the use of cannabis-based medicines for chronic pain (with and without meta-analyses) is outpacing that of randomised controlled trials. Furthermore, narrative reviews of public institution are largely based on these SRs, which often reach different conclusions regarding the efficacy and safety of cannabis-based medicines because of the lack of high-quality evidence of efficacy and the presence of indications that they may be harmful for patients. Societal safety concerns about medical cannabis (e.g. driving risks, workplace safety and pediatric intoxication) must always be borne in mind, and will probably not be addressed by clinical studies. Medical cannabis and cannabis-based medicines have often been legalised as therapeutic products by legislative bodies without going through the usual process of regulatory approval founded on the results of traditional evidence-based studies. This review discusses the advantages and limitations of using cannabis to treat rheumatic conditions.
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Expert Review of Clinical Immunology
ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20
Medical cannabis and cannabinoids in
rheumatology: where are we now?
Piercarlo Sarzi-Puttini, Alberto Batticciotto, Fabiola Atzeni, Laura Bazzichi,
Manuela Di Franco, Fausto Salaffi, Daniela Marotto, Angela Ceribelli, Jacob N
Ablin & Winfred Hauser
To cite this article: Piercarlo Sarzi-Puttini, Alberto Batticciotto, Fabiola Atzeni, Laura Bazzichi,
Manuela Di Franco, Fausto Salaffi, Daniela Marotto, Angela Ceribelli, Jacob N Ablin & Winfred
Hauser (2019) Medical cannabis and cannabinoids in rheumatology: where are we now?, Expert
Review of Clinical Immunology, 15:10, 1019-1032, DOI: 10.1080/1744666X.2019.1665997
To link to this article: https://doi.org/10.1080/1744666X.2019.1665997
Accepted author version posted online: 12
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Published online: 19 Oct 2019.
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REVIEW
Medical cannabis and cannabinoids in rheumatology: where are we now?
Piercarlo Sarzi-Puttini
a
, Alberto Batticciotto
b
, Fabiola Atzeni
c
, Laura Bazzichi
d
, Manuela Di Franco
e
, Fausto Salaffi
f
,
Daniela Marotto
g
, Angela Ceribelli
a
, Jacob N Ablin
h
and Winfred Hauser
i
a
Rheumatology Unit, ASST Fatebenefratelli-Sacco, University of Milan, Milan, Italy;
b
Rheumatology Unit, Internal Medicine Department, ASST
Settelaghi, Ospedale Di Circolo - Fondazione Macchi, Varese, Italy;
c
Rheumatology Unit, University of Messina, Messina, Italy;
d
Rheumatology Unit,
AOU Pisana, Pisa, Italy;
e
Department of Internal Medicine and Medical Specialities, Rheumatology Unit, Sapienza University of Rome, Rome, Italy;
f
Rheumatological Clinic, Università Politecnica delle Marche, Jesi, Ancona, Italy;
g
Rheumatology Unit, P-Dettori Hospital Tempio Pausania, Tempio
Pausania, Italy;
h
Internal Medicine H, Tel Aviv Sourasky Medical Center, Tel Aviv Israel;
i
Department of Internal Medicine 1, Klinikum Saarbrücken,
D-66119 Saarbrücken, Germany
ABSTRACT
Introduction: Clinicians involved in pain management can finally include cannabis or cannabis-related
products in their therapeutic armamentarium as a growing number of countries have approved them
for pain relief. Despite the several benefits attributed to analgesic, anti-inflammatory and immunomo-
dulatory properties of cannabinoids, there are still significant areas of uncertainty concerning their use
in many fields of medicine.
The biosynthesis and inactivation of cannabinoids are regulated by a complex signaling system of
cannabinoid receptors, endocannabinoids (the endogenous ligands of cannabinoid receptors) and
enzymes, with a variety of interactions with neuroendocrinological and immunological systems.
Areas covered: A review of studies carried out during clinical development of cannabis and cannabis
medical products in systemic rheumatic diseases was performed, highlighting the aspects that we
believe to be relevant to clinical practice.
Expert opinion: The growing public opinion, pushing toward the legalization of the use of cannabis in
chronic pain and various rheumatological conditions, makes it necessary to have educational programs
that modify the concerns and widespread preconceptions related to this topic in the medical commu-
nity by increasing confidence. More extensive basic and clinical research on the mechanisms and
clinical utility of cannabis and derivatives in various diseases and their long-term side effects is
necessary.
ARTICLE HISTORY
Received 31 March 2019
Accepted 6 September 2019
KEYWORDS
Cannabis; endocannabinoid
system; fibromyalgia; SLE;
rheumatoid arthritis;
cannabidiol;
tetrahydrocannabinol (THC)
1. Introduction
Clinicians involved in pain management can now include
cannabis or cannabis-related products in their therapeutic
armamentarium, as an increasing number of countries have
approved its use. However, despite the known analgesic, anti-
inflammatory and immunomodulatory effects, the uncertainty
and controversy surrounding the scientific data make it diffi-
cult to establish the role and appropriate use of cannabis in
the management of various diseases, particularly in the field of
rheumatology [1,2].
Pharmaceutical products usually go through a defined pro-
cess before being approved for therapeutic purposes, but
standard scientific scrutiny has been by-passed in the case of
cannabis, which has been approved with a variety of indica-
tions [14]. It is therefore important to collect further objective
data concerning the benefits and risks of using medical can-
nabis in order to be able to counsel patients and provide
appropriate clinical care.
This review will concentrate on the use of medical cannabis
and cannabis-based medicines in managing rheumatic condi-
tions, and highlight the aspects that we believe to be relevant
to clinical practice.
2. Legality of cannabis
The possession of Cannabis is considered a non-criminal
offense in many Western countries, while it is punished or
maybepunishedbyprisonincountriesintheMiddleEast
and Asia. On the other hand, the recreational use of cannabis
has been legalized throughout Uruguay, Luxembourg and
Canada, in the District of Columbia and in ten states in the
USA, and it is sold under license in Spain and The
Netherlands.
The medical use of cannabis has been legalized in
Australia, Canada, Chile, Colombia, Finland, Germany,
Greece, Israel, Italy, The Netherlands, Norway, Peru, Poland,
and Thailand [5], as well as in the District of Columbia and
33 states in the USA. In other countries only certain canna-
bis-derived pharmaceutical drugs such as Sativex, Marinol or
Epidiolex to be used.
3. The endocannabinoid system
Endocannabinoids (eCBs), their receptors, and the associated
mediating enzymes for synthesis and degradation comprise
the endocannabinoid system (ECS) (Figures 1 and 2).
CONTACT Piercarlo Sarzi-Puttini piercarlo.sarziputtini@gmail.com
EXPERT REVIEW OF CLINICAL IMMUNOLOGY
2019, VOL. 15, NO. 10, 10191032
https://doi.org/10.1080/1744666X.2019.1665997
© 2019 Informa UK Limited, trading as Taylor & Francis Group
Trans-Δ9-tetrahydrocannabinol (THC, the primary psychoactive
constituent of cannabis) was first isolated in the 1960s [6,7], and
the identification of cannabinoid receptors 1 and 2 (CBr1 and CBr2)
led to the isolation and characterization of their endogenous
ligands, the endocannabinoids N-arachidonoyl-ethanolamine
(AEA, also known as anandamide), 2-arachidonoylglycerol (2-AG),
2-archidonoylglyceral ether (noladin ether), O-archidonoyl ethano-
lamine (virodhamine) and N-arachidonoyl dopamine. Five main
enzymes are involved in their biosynthesis and inactivation: N-acyl-
phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-
PLD), sn-1-specific diacylglycerol lipase-α(DGLα), DGLβ, fatty acid
amide hydrolase 1 (FAAH), and monoacylglycerol lipase (MAGL,
also known as MGL) [810].
3.1. Cannabinoid receptor 1
The human cannabinoid 1 (CBr1) receptor, which is a G protein-
coupled receptor, is part of the endocannabinoid system (ECS),
Figure 1. Endocannabinoid system.
(1) Anandamide(A) and 2 Arachinodonoyl glycerol (2AG), themost know endocannabinoids, are synthesized on-demand tthrough the enzymatic hydrolysis of membrane precursors and released in the
intersynapticgap immediately afterproduction. The synthesis andrelease occurs following the increase of calcium. Thusreleasedendocannabinoidscan functionas retrograde messengers by binding to
presynaptic cannabinoid receptors,(2) which in turn inhibit the voltage-dependent calcium channels (Ca +) andactivate those of potassium (K +) (3). This effect on membrane polarization involves an
inhibition of the release of other neurotransmitters (such as glutamate, dopamine, GABA).(4) The neuromodulatory process of endocannabinoids ends with a re-uptake mechanism within neurons
through a possible transporter(5) and subsequent degradation.(6)
NAPE N-arachidonoylphosphatidylethanolamine(NAPE), PLD phospholipase-D, AA arachidonic acid, E ethanolamide, A Anandamide, FAAH fatty acid amide hydrolase enzyme,2 AG 2 Arachinodoyl
glycerol, GLYC glycerol, MAGL monoacylglycerol lipase, FAAH fatty acid amide hydrolase, MAGL monoacylglycerol lipase, CB1 Cannabinoids receptors.
CB1 CB2
Cerebral cortex, hippocampus,
amygdala, basal ganglia, substantia
nigra, globus pallidus, cerebellum
adipocytes, leukocytes, spleen,
heart, lung, the gastrointestinal
tract, kidney, bladder, reproductive
organs, skeletal muscle, bone,
joints and skin.
Tissues and cells of the
immune system
(leukocytes,spleen), liver,
nerve cells including
astrocytes,
oligodendrocytes and
microglia,
Euphoric effects; hypotensive; anti-
inflammatory; immunosuppressive; anti-
spastic; analgesic activity; stimulates appetite
anti-inflammatory and
immunomodulatory activity
Distribution
Functions
Figure 2. Endocannabinoid receptors distribution and related function.
1020 P. SARZI-PUTTINI ET AL.
which is highly regulatory in various functions throughout the
body. CBr1 is widely distributed in the brain and is predomi-
nantly expressed on axons and presynaptic terminals [1113].
The primary psychoactive component of cannabis, delta-
9-tetrahydrocannabinol (THC), binds to CBr1, and this bind-
ing in the CNS is responsible for the psychoactive effects of
cannabis.
The effects of CBr1 on the brain are predominantly facili-
tated by retrograde signaling (also called retrograde neuro-
transmission) induced by post-synaptic cell depolarization; this
leads to the post-synaptic production and release of endocan-
nabinoids, which activate pre-synaptic CBr1. CBr1 activation
has an inhibitory effect on pre-synaptic cells (Figure 1).
The deconstruction of CBr1 signaling reveals various mole-
cular pathways. Acting via Gi/o proteins, CBr1 activation inhi-
bits adenylate cyclase, reduces cell cAMP levels and,
subsequently, decreases the inhibitory activity of protein
kinase A (PKA), which increases the activity of A- type potas-
sium channels and leads to an overall decrease in cell potas-
sium levels [12,13].
Another route of CBr1 signaling is via the βγ subunit of
G protein-coupled receptor, which activates mitogen-activated
protein kinase (MAPK) and phosphoinositide-3-kinase. The
activation of CBr1 also has contrasting effects on cell ion
channels as it stimulates inward-rectification [12,13].
CBr1 is also expressed in other tissues, organs like the
thyroid and adrenal gland, liver, adipose tissue, the gastroin-
testinal tract, and the reproductive organs, as well as on
immune cells. An immunosuppressive function via CBr1 was
shown by endogenous and exogenous cannabinoids in sev-
eral studies [1319].
Its expression in the brainstem is relatively low, which may
account for the limited toxicity of cannabis and the absence of
respiratory suppression [20].
CBr1 are also found on the chondrocytes and osteocytes of
human joints and there is evidence suggesting that CBr1
facilitates the adhesion of fibroblast-like synoviocytes (FLSs)
to fibronectin, thus reducing the migratory capacity of these
cells and possibly decreasing cartilage destruction [21].
3.2. Cannabinoid receptor 2
CBr2 (also known as the peripheral cannabinoid receptor) is
another G protein-coupled receptor that has a 44% amino acid
similarity with CBr1. It acts in a similar manner to CBr1 by
inhibiting adenylate cyclase and activating MAPK, but its acti-
vation can also transiently increase intra-cellular calcium levels
via phospholipase C [22,23]. It is primarily expressed on
immune cells, but is also expressed on chondrocytes, osteo-
cytes, fibroblasts, FLSs, dorsal root ganglia, and microglial cells,
although the extent to which it is expressed in the human
nervous system is still unclear [18,20,21].
Evidence of CBr2 mRNA has been found in rodent cere-
bellum, cortex, brainstem, spinal cord and glial cells, and it
is worth noting that the Q63R variant is associated with
autoimmune diseases such as celiac disease, immune
thrombocytopenic purpura, and (of particular interest to
rheumatologists) juvenile idiopathic arthritis [23].
3.3. Other cannabinoid receptors
While It is agreed that CBr1 rand CBr2 are the two main
cannabinoid receptors, but there is still debate concerning
the identity of others [24], including:
Transient receptor potential cation channel subfam-
ily V member 1 (TRPV1) is a ligand-activated cation
channel that is mainly regarded as a pain receptor [25].
G protein-coupled receptor 55 (GPR55) is sometimes
referred to as a candidate CB3ʹreceptor [2,24,26].
Peroxisome proliferator-activated receptor-α(PPARα)
is a fatty-acid-activated transcription factor that is pre-
dominately expressed on skeletal muscles, but also in the
liver (it is the designated site of action of fibrates, the
fibric acid derivatives used to treat hypercholesterole-
mia) and on human chondrocytes and osteocytes [26].
3.4. Phytocannabinoids
The cannabis plant contains over 400 naturally occurring chemi-
cals and approximately 100 phytocannabinoids (Figure 3)[27
29]. Cannabis is the root word and the scientific plant genus from
which all other names derive. There are 3 subspecies of cannabis,
including Cannabis sativa, Cannabis indica, and Cannabis ruder-
alis. Cannabis sativa [28] is the most widely cultivated plant for
both commercial and pharmaceutical use. The best known
among phytocannabinoids are Δ9-tetrahydrocannabinol (THC)
and cannabidiol (CBD), which are already being used in medi-
cine: Δ9-THC is considered to be the main psychoactive compo-
nent of C. sativa because of its high affinity with and partially
agonistic effect on CBr1, whereas CBD is the main non-
psychoactive component and is characterized by a relatively
low affinity for cannabinoid receptors [29]. CBD acts as a partial
antagonist of CBr1 and a weak inverse agonist of CBr2, although
it can indirectly activate both by increasing AEA and 2-AG levels.
It is thought that THC and CBD have synergistic effects in which
other phytocannabinoids may participate, and this has given rise
to the theory of an entourage effectthat increases the benefits
of cannabis over synthetic cannabinoids [30].
The components that may contribute to the entourage effect
are the terpenoids and flavonoids. The former shares a common
precursor with phytocannabinoids and give cannabis its distinc-
tive aroma, but also induce medicinal effects (attributed to their
anti-inflammatory properties) and have modulatory effects on
THC. Cannabis leaves consist of ~1% flavonoids, and apigenin
and quercetin are the main flavonoids found in cannabis [29].
Some flavonoids may have anti-arthritic properties as arthritic
mice treated with a flavonoid extract from the Daphne genkwa
plant containing 29.51% apigenin had significantly lower arthritis
scores than controls [31,32].
3.5. Medical cannabis and cannabis-based medicines
Some confusion has arisen because the simple word cannabis
is used to describe both the drug of abuse unlawfully sold on
the street, and the plant and plant-based products used for
therapeutic purposes. It is therefore more appropriate to use
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1021
the term medical cannabisin the case of cannabis plants and
plant material, and the terms cannabis-derivedor cannabis-
basedmedicines in the case of medicinal cannabis extracts
whose THC and THC/CBD content have been standardized and
defined.
Furthermore, the fact that oils and extracts containing small
or not clearly specified amounts of CBD can be legitimately
sold as nutritional supplementshas only added to the
confusion.
3.6. Synthetic and semi-synthetic cannabinoids
Excluding off-the-shelf cannabinoid supplements, three cannabi-
noid products (synthetic cannabinoids and phytocannabinoids)
have been approved for medical use. Nabiximols is the only one
that consists of natural THC and CBD extracted from cannabis,
whereas dronabinol being plant-derived but chemically modified
during extraction, is considered a synthetic THC, and nabilone is
a synthetic cannabinoid resembling THC [33,34].
Dronabinol (Marinol) is the main isomer of tetrahydrocan-
nabinol, the main psychoactive constituent of the marijuana
plant (Cannabis sativa)[35]. It is a partial agonist of the cannabi-
noid receptors in the central nervous system (CB1) and periphery
(mainly CB2). Activated CB receptors have effects on appetite,
mood, cognition, memory and perception. The current indica-
tions of dronabinol, which was approved for use in the United
States in 1985 and is available generically and under the brand
name Marinol in the form of 2.5, 5 and 10 mg capsules, are
anorexia with weight loss in AIDS patients, and the prevention
of cancer chemotherapy-associated nausea and vomiting. There
is no convincing, unbiased, high quality evidence suggesting
that cannabinoids are of value for anorexia or cachexia in cancer
or HIV patients. An overview of systematic reviews of RCTs con-
cluded that, with safe and effective antiemetics available, CBs can
be recommended as a third-line treatment in the management
of breakthrough nausea and vomiting but, given the lack of RCT
data and safety concerns, herbal cannabis cannot be recom-
mended for CINV. The typical twice-daily adult oral dose of
2.5 mg can be increased up to 20 mg/day depending on toler-
ability and effect. The most frequent side effects are drowsiness,
fatigue, dizziness, conjunctivitis, abnormal thinking and paranoid
reactions, euphoria, nausea, vomiting, abdominal pain and diar-
rhea; hallucinations and seizures are rare side effects include
[33,34].
Namisol® is the worlds first oral tablet containing fixed
doses of pure natural Δ9-THC (dronabinol) that ensure
a predictably high level of bioavailability and a long and
stableshelflifeatroomtemperature.Itisduetoberegis-
tered for a number of indications, including MS, behavioral
disturbances in patients with Alzheimersdisease,and
chronic pain [28,33,36].
Nabilone (marketed as Cesamet in Canada, Mexico, the UK
and the USA) is a synthetic cannabinoid that is therapeutically
used as an anti-emetic and adjunctive analgesic for neuro-
pathic pain. It mimics the main ingredient of THC, but has
more predictable side effects and causes minimal or no
euphoria. It was approved by the American Food and Drug
Administration (FDA) for the treatment of CINV not respond-
ing to conventional anti-emetics in 1985, but was not mar-
keted for this use until 2006; it is also approved for the
treatment of anorexia and weight loss in patients with AIDS.
Although only Mexico and Belgium have officially approved
the indication, it is currently widely used as an adjunct in the
management of chronic pain, although trials and case studies
have shown conflicting results on potential benefits in condi-
tions such as fibromyalgia and multiple sclerosis (MS) [29,33].
Nabiximols (trade name Sativex) is a cannabis extract
approved in the UK in 2010 as a botanical mouth spray
designed to alleviate neuropathic pain, spasticity, an overac-
tive bladder, and other symptoms of MS. It has a standardized
Δ9-THC
Psychoactive effects
CBN
(
derived from Δ9-THC oxidation)
Possible immunosuppressive
properties
(in vitro studies )
CBD
NO psychoactive effects
Possible anti- inflammatory,
analgesic, anti-nausea, anti-emetic,
anti-psychotic, anti-ischemic,
anxiolytic, and anti-epi leptiform
effects
CBG, CBC
OTHER CONSTITUENTS
Nitrogenous compounds, amino acids,
proteins, enzymes, glycoproteins,
hydrocarbons, simple alcohols,
aldehydes, ketones a nd acids, fatty
acids, simple esters and lactones,
steroids, non-cannabinoid phenols,
flavonoids, vitamins, and pigments
TERPENES
anti-oxidant; anti-anxiety, anti-inflammatory, anti-bacterial, anti-
neoplastic, anti-malarial (few in vitro and in vivo studies);
responsible for differences in fragrance among cannabis plants,
and may somehow modify or enhance the physiological effects of
the cannabinoids.
THCV
NO psychoactive effects
anti-epileptiform/anti-convulsant
properties
Figure 3. Pharmacological actions of the various cannabis Sativa compounds.
Abbreviations: CBD: cannabidiol; CBN: cannabinol; THCV: Tetrahydrocannabivarin; CBG: cannabigerol; CBC: cannabichromene; Δ9-THC: Delta-9-tetrahydrocannabinol
1022 P. SARZI-PUTTINI ET AL.
composition, formulation and dose, and its main active canna-
binoid components are THC and CBD; each spray delivers
2.7 mg of THC and 2.5 mg of CBD [28,3335].
3.7. Natural cannabinoids
Many types and strains of medicinal cannabis (with THC and
CBD contents of respectively 1-22% and 0.05-9%) can be pre-
scribed in different European countries [33]. Table 1 shows the
main natural cannabinoids available in Italy. The leaves and
flowers contain many molecules, of which THC and CBD are
the most studied. In addition to THC and CBD, herbal cannabis
contains many non-cannabinoid molecules, with physiologic
effects that are largely unknown.
Medical cannabis refers to the whole plant or extract
thereof, used for medical purposes as dried flowers and leaves
or an oil extract, and may be administered by smoking, inhala-
tion through a vaporizer (heating to lower temperatures than
smoking), ingestion, or topical applications. Cannabinoids are
also available as pharmaceutical quality preparations, either as
plant extracts with specified doses of THC and CBD, or synthe-
sized products acting on cannabinoid receptors [36]. The
choice may depend on age, co-morbidities, tolerance, pathol-
ogy and symptomatology.
Of all the different routes of administration (oral, topical,
rectal, vaginal, sublingual, inhalation), the oral and the inhala-
tion by vaporization routes are the most used. Both methods
provide for the heating of cannabis, an operation necessary for
the decarboxylation (total or partial) of cannabinoids con-
tained in plant derivatives.
Depending on the route and the form of administration,
various modifications can be made to the chemical composi-
tion of cannabis and, consequently, to the effect obtained [36].
Each mode of administration and formulation has its
strengths and drawbacks [3638]. The oral formulations available
are capsules and liquid extract (tinctures, cannabis raw papers
useful to be infused in drinks, oil), resin, edible (e.g. biscuits,
chocolates, cannabis, juices, raw cannabis). The oral formulations
of cannabis take at least 30 to 90 minutes before any effects are
felt, reaching peak effect after 24 hours from intake. Given these
properties oral administration is useful for chronic conditions
requiring higher dosage and longer half-life; at the same time
overdosing is much more common than inhalation. For this
reason, its important to allow at least three hours from one
administration to another.
Another disadvantage is that the delayed onset of action
makes dose titration difficult and makes them little useful in
some conditions e.g. nausea or muscle spasm that require
rapid onset of action. In this case, oro-mucosal or sublingual
administration are preferable because of their faster action
and uptake; formulations available are lozenges, lollipops,
drops, oil and spray pump.
The extract in oil is a very concentrated medicine and it is the
easiest to dose and the most practical in the intake. It involves
the extraction in the laboratory by means of oily solvent of the
active ingredients starting from the inflorescences. There are
different methods of extraction, which influence the concentra-
tion of the final product. The preparation using the Roman and
Hazekamp method involves a hot extraction by olive oil, with
a solvent cannabis ratio of 1:10 (5-10g of Cannabis in 50100 ml
of olive oil.) The process involves grinding Cannabis with
a grinder to obtain a finer raw material and to increase the
surface of contact with the solvent and to facilitate its action.
The cannabis is added to the olive oil, heated to 98°C in a water
bath for 120 minutes, cooled down and filtered under pressure
to recover the oil of which the Cannabis remains impregnated.
Different types of Cannabis can be used with this method.
Oil type, heating times, techniques and extraction mechanics
can vary with variable oil concentrations.
The resin obtain by the described method is generally
dispensed in 1 ml syringes and it is black for the presence of
chlorophylls. The dosage is extremely variable: generally the
minimum dose is a drop, increasing by approximately 1 drop
every 34 days, evaluating any side effect or the appearance
of psychotropic effects, nausea, vomiting or loss of appetite.
The heating of the plant at 200 C° reached with the vaporiza-
tion allows the liberation of the cannabinoids and terpenes in
the form of vapor, their rapidly absorption by the lungs and
distribution in the whole body.
The effect is rapid but not lasting, indeed first effects occur
within 90 seconds and reach a maximum after 1530 minutes,
wearing off in 24 hours. For this reason vaporizing cannabis
products is best in acute conditions where rapid relief is
required. Inhaled administration requires a vaporizer and
there are a wide variety of vaporizers commercially available.
The Volcano is approved as a medical device.
The recommended operating temperature of the device is
about 210°C: this allows the emission of a barely visible steam
(a light mist) and the extraction of all cannabinoids, represent-
ing the ideal balance between aroma and quantity extracted.
Technically it is possible to use the vaporizer at different
temperatures (e.g. 190°C or 230°C), thus changing the quantity
and type of substances extracted. It is recommend starting
with one or two vaporizations per day, with an interval of 5 to
10 minutes between one inhalation and another. After about
1 week a constant concentration of active ingredients is
reached and the dosage can be reassessed if it proves
unsatisfactory.
Table 1. Varieties of cannabis and related THC and CBD concentrations, terpenic
profile and countries of origin available in Italy.
Variety THC CBD
Terpenic
profile Provenance
Bedrocan = 22% <1% Sativa Netherlands
Bedrobinol = 12% <1% Sativa Netherlands
Bediol = 6.5% = 8% Sativa Netherlands
Bedica = 14% <1% Indica Netherlands
Bedrolite <1% = 9% Sativa Netherlands
FM2 5-8% 7.5-12% Sativa Italy
FM1 13-20% <1% Sativa Italy
Pedanios
Aurora
= 22% <1% Sativa Canada
Pedanios
Aurora
= 8% = 8% Indica Canada
Pedanios
Aurora
<1% = 9-12% Hybrid Canada
The inflorescences are changed into 0.50.4 mm granules,and dispensed as
capsule or pods (bedrolite and bediol are already granular).
All can be extracted in oil using the SIFAP ethod:70 mg/ml-1gtt = 2.5 mg-12 gtt
30 mg
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1023
The topical formulations comprise eye drops, gel and cream.
The cannabis eye drops are an oil-based drug which, once
prepared, is cold sterilized by means of micropore filtration
under a sterile laminar flow hood. A very small percentage of
surfactant is added to it to make the oil adhere better to the
water.
Usually, 12 drops per eye are applied, one or more times
a day according to medical prescription.
The main side effects are related to the initial burning that
can be felt due to the acidity of the oil; generally it disappears
in a few seconds and after a few weeks of use, it tends not to
appear further. It must be shaken energetically 56 times each
time before being administered, to favor the re-solubilization
of eventual formations of zones of different concentration.
Transdermal gel is an innovative and experimental approach
to cannabis intake at the local level (on the skin) and systemic,
since the gel is transdermal, which prefers a high absorption
of substances to reach the blood vessels and, from there, all
the body. Being an experimental drug, the precise amounts
absorbed are not yet known. The main side effect can be as
follows: redness or itching in the area of application (rare) [39].
The dosage of Cannabis derivatives is extremely variable
and depends on numerous factors that contribute to deter-
mining the dosage (sex, age and weight of the patient, nature
of the disease, type and severity of symptoms, concomitant
therapies, route of administration) Therefore dosing is highly
individualized and relies on titration of the product [40].
The first problem in the choice of dosage is to try to
standardize the dosage by disease. This approach is found to
be unsuccessful in the case of cannabis because it is not
administered as a drug with only one active ingredient, but
hundreds of substances that act in synergy.
Using the premise starting low and going slowCannabis
dose should be increased gradually until the prescribed optimal
dose, where therapeutic effect is maximized and adverse effects
are minimized, is reached. Although the methods of consump-
tion most commonly used are vaporization and smoking of
cannabis we strongly contraindicate them because of the high
variance of bioavailability, the short-term supratherapeutic
plasma levels and the possible carcinogenic effects.
The regulatory frameworks normalizing the dispensing of
cannabis and cannabinoids for medical purposes and the
processes that led to their promulgation are different among
various nations [41]. Since the chemist Raphael Mechoulam
identified Tetahydrocannabinol (THC) in the early 1960s, Israel
has always represented a pioneering country adopting
a constantly evolving policy to allow the medical use of can-
nabis and cannabinoids. The Israeli system is an example of
synergy between government, physicians, cannabis growers
and suppliers and patients. Under the control of Israeli Medical
Cannabis Agency (IMCA) a unit within the Ministry of health,
Israel was one of the first countries to legalized the medical
use of cannabis. The IMCA controls the production of cannabis
and authorizes some cultivators, that must follow the indica-
tions of IMCA guide Medical Grade Cannabis Cannacopeia, to
supply it to authorized pharmacies.
The cannabis is distributed in two forms: as an oil for oral
intake or as dried flowers for smoking or vaporization. The
number of physicians authorized to prescribe (at present are
30) for these indications are limited.
In Canada, the legalization process of medical cannabis
started in 2000 and has changed over the years under pres-
sure of patients and court pronouncements. Since 2014, more
growers of cannabis have been authorized and more prescrip-
tion freedom has been given to medical and nurse practi-
tioners; federal supervision has been removed and patients
are allowed to buy cannabis directly from authorized produ-
cers. In this way the responsibility for the use of medical
cannabis has been transferred to the medical community.
At the same time, the Canadian Parliament is engaged in
an awareness campaign against possible damage related to
recreational use of cannabis and in 2018 it approved the
Cannabis Act (Bill C45) to legalize and regulate this use.
In Italy, with ministerial decree 23/01/2013, the use of
cannabis for therapeutic purposes was made official and
included in Table II, section B, among the drugs of plant origin.
Successive decrees of 2015 and 2016 have regulated the
cultivation and preparation of derived products, defined the
costs and production quotas and the pathologies for which
their use is allowed.
The reimbursement to be paid by the National Health
Service is subject to the indications of the individual regions.
Each specialist is qualified for prescription, which must be
drawn up according to specific regulations. A prescription should
only be provided by a physician who is fully knowledgeable of the
patient and is responsible for patient care. The medical encounter
must include documentation of the medical condition, reason for
medical cannabis consideration, associated comorbidities, current
medications, and previous treatment trials.
The varieties of medicinal cannabis prescribed in Italy are
listed in Table 1. FM2 cannabis produced by the military phar-
maceutical plant in Florence consists of unfertilized, dried and
ground female inflorescences with particles smaller than 4 mm,
containing acid precursors of delta-9-tetrahydrocannabinol
(THC) corresponding to a percentage of THC between 5 and
8% and cannabidiol (CBD) corresponding to 7.5 12%.
Cannabis should not be smoked, because of the toxic pro-
ducts of combustion. Inhalation through a vaporizer is preferred,
because less intensive heating reduces release of toxic combus-
tion products. Inhaled cannabis, through a vaporizer, will give
effects within a few minutes, with effects lasting up to a few
hours, although the psychoactive and motor effects may last for
over 24 h. The effects of ingested cannabis will occur more slowly
and be more prolonged, and may be the preferred method of
administration for a treatment regimen. Although there is no
evidence to support the therapeutic effect of various concentra-
tions of THC and CBD in the herbal product, cannabis with a low
THC content and higher CBD content is preferable because there
will be fewer and less severe THC-induced psychoactive effects.
Studies to date have reported on THC content up to 12.5%, but
with a high rate of adverse events at this concentration [42].
The ideal dosing schedule for medical cannabis is unknown,
with no dose-finding studies to examine optimal daily amount
or specific molecular concentrations of THC and CBD6. Some
patients may choose on-demanduse rather than regular use,
but there is no evidence to support this method.
1024 P. SARZI-PUTTINI ET AL.
4. The use of cannabis in rheumatic diseases
4.1. Rheumatoid arthritis
Rheumatoid arthritis (RA) is still a major health burden that affects
quality of life and consumes healthcare resources; it can cause
pain, joint malformations and joint destruction, and is one of the
main causes of disability worldwide [43]. The anti-inflammatory
effects of Cannabinoids have been shown in animal models of
arthritis [44]. According to in vitro studies, cannabinoids reduce
cytokine production by RA fibroblasts as well as the release of
matrix metalloproteinases (MMPs) from fibroblast-like synovial
cells (FLSc) [4547]. Cannabinoids have also been shown to
reduce interleukin 1 (IL-1) induced proteoglycan and collagen
degradation in bovine cartilage, thus reducing cartilage extracel-
lular matrix (ECM) breakdown [48]. One study has found AEA,
2-AG, CB1 and CB2 protein and mRNA expression in synovial
tissue obtained from 13 RA patients undergoing arthroplasty,
whereas synovial tissue obtained from healthy volunteers was
negative for AEA and 2-AG [49].
The precise role of the cannabinoid system is still unclear,
but these findings suggest that cannabinoids could potentially
be used in the treatment of RA (49). In a separate study of
synovial tissue taken from RA patients, the production of IL-6
and IL-8 by stimulated synovial cells was attenuated by low
concentrations of WIN 55,2122 mesylate, and high concen-
trations led to their CB2-dependent inhibition [50]. These
results are supported by various in vivo and in vitro experi-
mental studies. Three research groups have used a murine
model of collagen-induced arthritis (CIA) and observed clinical
improvements after treatment with various cannabinoids:
exposure to cannabidiol or the CB2 agonists JWH-133 or HU-
308 reduced disease severity, inflammatory cell infiltration,
bone destruction, the production of anti-collagen type II
IgG1 and IFNγ, and the release of TNF [5153].
Furthermore, a 5-week study of 58 patients found that nabix-
imols oromucosal spray was significantly superior to placebo
and significantly improved pain on movement and at rest,
DAS28 and SF-MPQ pain scores, and the quality of sleep. Most
of the adverse effects were mild or moderate, none of them was
serious, and none led to treatment discontinuation [54].
No randomized clinical trials (RCTs) of other cannabis-based
medicines are available.
4.2. Osteoarthritis
Osteoarthritis (OA) is a high prevalent rheumatic disease but
treatment is mainly based on analgesia because no disease-
modifying intervention has yet been discovered [55]. OA
seems to be the most frequent rheumatic disease treated
with cannabis [56,57], The endocannabinoid system may be
a therapeutic target as both CBr1 and CBr2 are expressed in
osteoarthritic synovia, and 2-AG and AEA have been found in
the synovial fluid of OA patients but not in that of healthy
volunteers [49]. In line with these findings, CBr1 and CBr2 are
also expressed in the chondrocytes of patients with OA [56].
The possibility of using cannabinoids in the treatment of OA is
further supported by the results of a 2015 study of a murine
model of surgically induced OA (destabilization of the medial
meniscus) in which the mice treated with the CBr2 agonist HU-
308 showed milder disease than those treated with vehicle,
and CBr2-deficient mice had a more severe form of OA than
their wild-type counterparts [58].
Various mechanisms have been suggested to explain the
possible therapeutic effects of cannabinoids. Exposure of OA
chondrocytes to WIN 55,2122 mesylate [56,59] reduced the
activity of metalloproteinases and nitric oxide production in
bovine chondrocytes [57]. Another possible pathway is chon-
drocyte apoptosis as it has been shown that AEA decreases
the viability of murine chondrocytes, and thus potentially
contributes to cartilage destruction [60].
4.3. Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a chronic autoimmune
disease characterized by various clinical manifestations that
can involve different organs and systems [61]. Key features
of SLE seem to be the abnormal formation of extracellular
neutrophil traps, defects in apoptotic clearance, and a type 1
interferon (IFN) signature, which can lead to a loss of tolerance
and consequent B and T lymphocyte abnormalities [62,63].
A recent study has found that plasma 2-AG levels are signifi-
cantly higher in SLE patients than in healthy subjects (p = 0.0059).
and that the patients with the highest levels had less active
disease; there were no between-group differences in the concen-
trations of N-arachidonoylethanolamine (AEA) or its congeners
N-palmitoylethanolamine (PEA) and N-oleoylethanolamine
(OEA). A gene expression analysis of metabolic enzymes and
the receptor targets of eCBs, and an investigation of the func-
tional activity and protein expression of selected components of
the eCB system, revealed that the expression and functional
activity of the 2-AG biosynthetic enzyme DAGL were selectively
enhanced in the PBMCs of the patients. This study demonstrates
for the first time that SLE patients have an altered ECS [64], and it
is interesting to note that modulating CBr2 expression certainly
provides a biochemical and molecular basis justifying a planned
phase II clinical trial (NCT03093402) designed to evaluate the
efficacy, safety and tolerability of a new and highly purified
composition of ajulemic acid (a synthetic non-psychoactive can-
nabinoid) in SLE patients [65].
4.4. Systemic sclerosis
Systemic sclerosis(SSc) is an immune-mediated, rare, systemic
disease with an unknown etiology, characterized by excessive
fibrosis, extra-cellular matrix deposition, and vasculopathy also
known as scleroderma to emphasize the hard appearance
taken on by the skin [66]. It has a high morbidity and mortality
mainly related to visceral involvement [67].
One of the pathways being explored in SSc treatment research
is the endocannabinoid system. It has been shown that CBr1 and
CBr2 modulate SSc in various murine models. CBr1 activation
seems to exacerbate fibrosis, and CBr1-deficient mice show
decreased dermal thickening [68]. Unlike CBr1, CBr2 may protect
against SSc: CBr2-deficient mice injected with bleomycin show
increased dermal thickness and have higher leukocyte counts in
skin lesions, and treating wild-type mice with the CBr2 agonist
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1025
JWH-133 reduces leukocyte infiltration and dermal thickening [69].
Similar results have been obtained in mice treated with VCE-004.8,
adualagonistofPPARγand CBr2 that reduces dermal thickness,
collagen accumulation in blood vessels, skin macrophage infiltra-
tion, and mast cell degranulation [70]. JHW-133 also prevents the
development of skin and lung fibrosis and reduces anti-DNA
topoisomerase antibody levels and fibroblast proliferation in
a murine model of hypochlorite-induced fibrosis [71].
CBr2 may potentially be a key modulator of fibrogenesis.
Wounded mice treated with the CBr2 agonist GP1a showed
reduced fibroblast accumulation, fibroblast-to-myofibroblast
transformation and collagen deposition, and lower levels of
transforming growth factor-β1 (TGFβ1), IL-6, TNF and vascular
endothelial growth factor [72,73].
In comparison with fibroblasts from healthy subjects, ana-
lyses of biopsied human skin reveal an over-expression of CBr1
and CBr2 in the fibroblasts of patients with diffuse cutaneous
SSc (dcSSc), and treating the fibroblasts with WIN 55,2122
mesylate decreased extra-cellular matrix deposition, myofibro-
blast differentiation, and resistance to apoptosis [73,74].
Lenabasum (JBT-101) is a selective cannabinoid receptor type 2
agonist which is undergoing clinical investigations for the treat-
ment of systemic sclerosis (the RESOLVE-1 trial NCT03398837) as
well as in additional rheumatologicalconditionssuchasdermato-
myositis (NCT03813160) and SLE (NCT03093402). Thus, selective
cannabinoid receptor agonists may gain an increasing future role
as targeted treatment for systemic autoimmune disorders.
4.5. Fibromyalgia (FM)
FM is a chronic syndrome of unknown pathophysiology that is
characterized by widespread pain, morning stiffness, fatigue,
sleep and emotional disturbances and cognitive dysfunction
[75]. It has been suggested that it may be related to the
suppression of descending inhibitory pathways, central sensi-
tization, excessive glial cell activity, abnormal neurotransmitter
release, and/or an abnormal stress response [76]. Currently,
the treatment is based on the relief of symptoms but poor
results are achieved. Given its unknown pathophysiology and
the absence of suitable treatment, cannabis (which is fre-
quently used for analgesic purposes) is a natural therapeutic
candidate, and its medicinal use for FM has been approved in
a number of countries [7784].
All of the clinical trials investigating the effectiveness of
cannabinoids in the treatment of FM have used nabilone.
A placebo-controlled study of 40 FM patients investigated
the results of four weekstreatment with nabilone. The
authors reported that nabilone led to a statistically significant
improvement in pain relief in pre- and post-treatment com-
parison [84], but a re-analysis of the mean values and standard
deviations described in the paper found that there was no
statistically significant difference. Furthermore, another study
of 32 patients found no statistically significant difference
between nabilone and amitriptyline in terms of reduced pain
after two weeks [85].
However, as the small sample sizes and short duration pre-
cluded unbiased conclusions, the studies did not support the use
cannabinoid treatment for FM [83]. On the contrary, a US
government-sponsored committee concluded that there is mod-
erate-grade evidence supporting the effectiveness of cannabi-
noids [86].
One observational study that did not meet the inclusion
criteria for the Cochrane review compared 28 FM patients who
used cannabis with 28 who did not. Two hours after cannabis
self-administration, the cannabis users reported a reduction in
pain and stiffness and increased relaxation, accompanied by
greater somnolence, feelings of well-being, and SF-36 mental
health component scores; however, there were no improve-
ments in the other components of the SF-36, in FIQ scores, or
in the Pittsburgh Sleep Quality Index [87].
An experimental, randomized, placebo-controlled, 4-way cross-
over trial investigated the analgesic effects of inhaled pharmaceu-
tical-grade cannabis in 20 FM patients suffering from chronic pain
[88]. They received four different cannabis varieties whose THC and
CBD contents were known: Bedrocan (THC 22.4 mg, CBD <1 mg;
Bedrocan International BV, Veendam, The Netherlands), Bediol
(THC13.4mg,CBD17.8mg;BedrocanInternationalBV,
Veendam, The Netherlands), Bedrolite(CBD18.4mg,THC<1mg;
Bedrocan International BV, Veendam, The Netherlands), and
a placebo without any THC or CBD. Plasma THC and CBD concen-
trations, the thresholds of pressure and electrical pain, sponta-
neous pain scores, and drug highs were measured for three
hours after a single inhalation of vapor. None of the treatments
had more than a placebo effect on responses to spontaneous or
electrical pain, but Bediol showed an additional 30% pain decrease
over placebo (90% vs 55%, P = 0.01), and the spontaneous pain
scores correlated with the extent of the drug highs (ρ=0.5,
P < 0.001). The cannabis varieties containing THC significant
increased pressure pain thresholds in comparison with placebo
(P < 0.01). CBD inhalation increased plasma THC concentrations,
but reduced the analgesic effects induced by THC, thus indicating
synergistic pharmacokinetic but antagonistic pharmacodynamic
interactions. The trial showed the complex behavior of inhaled
cannabinoids in chronic pain patients, with just a small analgesic
response after a single inhalation, but there is a need for further
studies in order to determine the long-term effects of treatment on
THC-CBD interactions and spontaneous pain scores, and the role of
psychotropic symptoms in relieving pain [88].
Many FM patients suffer from low back pain (LBP), and
a recent observational cross-over study of such patients has
assessed the possible improvement in pain and function asso-
ciated with medical cannabis therapy (MCT). Thirty-one
patients received standardized analgesic therapy (SAT: oxyco-
done hydrochloride 5 mg [equivalent to oxycodone] and
naloxone hydrochloride 2.5 mg twice daily and once-daily
duloxetine 30 mg) for three months, after which they could
choose to be given MCT for a minimum of six months. The
patient reported outcome (PRO) instruments were the revised
Fibromyalgia Impact Questionnaire (FIQR), a visual analog
scale (VAS), the Oswestry Disability Index (ODI) and the 12-
item Short Form Survey (SF-12), and their lumbar range of
motion (ROM) was measured using the modified Schober test.
SAT led to a minor improvement from baseline, but the addi-
tion of MCT significantly improved all of the PROs after three
months, and the effect was maintained for up to six months.
ROM also improved after three months of MCT and continued
1026 P. SARZI-PUTTINI ET AL.
to improve after six months [89]. These results show that MCT
has an advantage over SAT in FM patients with LBP, but
further randomized clinical trials are needed to establish
whether these can be generalized to the FM population as
a whole [90].
No RCTs of other cannabis-based medicines are available.
In Table 2, the possible mechanism of cannabinoid action
in different rheumatic conditions are summarized.
5. Adverse events
In the literature, there are a limited number ofstudies on adverse
events associated with the use of therapeutic cannabis [85]. Most
of the data come from studies related to recreational use.
Furthermore, while there is some information on short-term
side effects, there is much less information on the long-term
consequences. A two-fold higher rate of non-serious adverse
events in patients using medical cannabis compared to controls
was described in a Canadian systematic review [91]. The data on
short-term effects of medical use of cannabinoids and cannabis
have been collected from randomized controlled clinical trials in
different medical conditions conducted usually for periods of 8
to 12 weeks. The adverse events reported were usually minor
and the most frequent was dizziness. Other adverse events fre-
quently described were nervous system disorders, psychiatric
disorders, gastrointestinal disorders and vascular and cardiac
disorders. Another important consideration in the estimation of
adverse effects related to cannabis use is the concomitant use of
tobacco, alcohol and other drugs.
Tables 3 and 4report the major adverse effects of the
medical use of cannabis and cannabinoids. Table 5 describes
the possible interaction with other pharmacological products.
5.1. Cardiovascular effects
Tachycardia and hypotension are common adverse events
related to the use of cannabis and in patients with heart
disease could compromise their cardiovascular status.
A temporal relationship has also been shown between
acute cannabis use and increased risk of myocardial infarc-
tion and reduction of exercise competence in patients with
angina pectoris.
5.2. Cancerogenesis
Starting with the evidence that cannabis smoke condensates
contain many of the same chemicals as tobacco smoke, some
in vitro studies have shown strong evidence that smoke can-
nabis is carcinogenic and, lately, a comparison regarding the
cytotoxic and mutagenic potential effects of cannabis smoke
condensates and their tobacco equivalent has shown a higher
risk for cannabis smoke.
Evidence from in vivo studies are conflicting but despite
these it is suitable to discourage cannabis smoke. One study
has assessed the relationship among cannabis use and testi-
cular cancer [92]; a large population-based case-control study,
it didnt find a significant relationship between cannabis use
and lung cancers.
5.3. Pregnancy and breastfeeding
An increased risk of some congenital birth defects may be
associated with its use during early pregnancy, although THC
does not seem to show significant teratogenic effects [93].
Human and animal neurodevelopmental data suggest that
prenatal exposure to THC may lead to subtle but persistent
changes in targeted aspects of higher-level cognition and
psychological well-being [94]. Consequently, pregnant
women or women considering pregnancy should be encour-
aged to stop using THC for medicinal purposes in favor of an
alternative treatment for which there are better pregnancy-
specific safety data.
There are only limited and inconsistent data concerning the
presence of the constituents of cannabis-based medicines in
human milk, or their effects on milk production or breastfed
infants. Breastfeeding should be discouraged during treat-
ment with cannabis-based medicines [95].
Early, frequent and heavy recreational use of cannabis dur-
ing adolescence has been associated with poor cognitive and
psychiatric outcomes in adulthood [9698], but no definite
conclusions can be drawn as to whether its use alone nega-
tively affects human adolescent brains. Children and adoles-
cents should only be treated with cannabis-based medicines
in exceptional cases.
In conclusion the frequent adverse events related to phar-
maceutically prepared cannabinoid treatments are usually not
serious, but may be sufficient to affect patient well-being.
A meta-analysis by Fitzcharles et al. has revealed that 25-50%
of subjects experience side effects, mainly dizziness, drowsi-
ness and some form of cognitive effect, and other studies have
reported dry mouth, nausea and constipation. It is reassuring
to note that none of the studies of cannabis-based medicine
Table 2. Possible mechanisms of cannabinoids action in different rheumatic
diseases.
Possible Cannabinoids Action
Rheumatoid arthritis Reduction of:
cytokine production by RA fibroblasts, release MMPs
from fibroblast-like synovial cells,
interleukin 1 (IL-1) induced proteoglycan and col-
lagen degradation,
cartilage extracellular matrix (ECM) breakdown
Osteoarthritis Possible pathway:
Exposure of OA chondrocytes to WIN 55,2122
mesylate reduced the activity of metalloproteinases
and nitric oxide production
chondrocyte apoptosis (AEA decreases the viability of
murine chondrocytes, and thus potentially contri-
butes to cartilage destruction)
Systemic lupus
erythematosus
Modulation of 2 AG levels, CBr
2
expression
Systemic sclerosis Downregulation of CBr1and upregulation of CBr-2
expression reduces leukocyte infiltration and dermal
thickening,collagen accumulation in blood vessels,
skin macrophage infiltration, and mast cell
degranulation, prevents the development of skin
and lung fibrosis and reduces anti-DNA
topoisomerase antibody levels and fibroblast
proliferation
Fibromyalgia Pain relief
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 1027
have encountered any serious adverse events [99], but it must
be noted that the development of a new class of agents
designed to manipulate the endocannabinoid system
[26,29,33,50], which includes selective synthetic cannabinoid
receptor agonists or antagonists, inhibitors of catabolism (e.g.
fatty acid amide hydrolase [FAAH] inhibitors), or the reuptake
of endogenous cannabinoid ligands (endocannabinoids), may
be associated with more severe risks.
Presently, no clinical guidelines occur to monitoring
patients who are taking cannabis for medical purposes so is
necessary to carefully evaluated the risk/benefit ratio before
prescribing medical cannabis [100]. Must be taken into
account medical conditions, different variation in response
and tolerance to its effects. Contraindications to cannabis
use are shown in Table 6.
6. Conclusions
It is currently difficult to recommend cannabis-based medi-
cines for the treatment of patients with musculoskeletal pain
and/or systemic autoimmune diseases, and there is still a need
for larger, well-controlled clinical trials in order to clarify the
potential benefits and risks; in fact, no definite conclusion can
be drawn on the basis of meta-analyses and of the available
studies. New pharmacological analgesics (including cannabis
and cannabis-based drugs) can be helpful and should not be
abandoned only because of prejudice and misconceptions. It
is important to separate the recreational and medical use of
cannabis in research, and in all discussions with patients and
health authorities. Furthermore, although the debate is open,
research is starting, and patients have important and relevant
demands; however, the lessons learned from the opioid epi-
demic need to be remembered in order to avoid a cannabis
crisis.
In the face of patient demands, medical cannabis represents
a challenge for physicians. About 75% of surveyed rheumatolo-
gists say that they lack confidence regarding cannabinoid treat-
ment and consequently do not recommend it. It is necessary to
take into account possible adverse effects, interactions with
other drugs, and the risk of addiction due to the unique char-
acteristics and chronicity of rheumatic diseases, and the poten-
tial benefits of cannabinoid therapy must be weighed against
these risks. Cannabinoids have various effects on immune cells
that lead to an overall anti-inflammatory effect, and their immu-
nomodulatory properties are substantiated by studies of animal
models of systemic rheumatic diseases, but their possible use in
humans has hardly been explored. Surprisingly, despite the high
prevalence of cannabis consumption and the fact that
Table 3. Adverse effects of the medical use of cannabis and cannabinoids.
AE OR Short/Long Term References
Psychoses 1.4 to 3.4 S Marconi 2016 [101]
Dizziness 5.09 S/L Whiting 2015 [102]
Dry Mouth 3.5 S/L Whiting 2015
Nausea 2.08 S/L Whiting 2015
Fatigue 2.00 S Whiting 2015
Somnolence 2.83 S Whiting 2015
Vomiting 1.67 S Whiting 2015
Diarrhea 1.65 S Whiting 2015
Euphoria 4.08 S Whiting 2015
Bipolar Symptoms 3.0 S Gibbs 2015 [103]
Depression 1.3 S/L Lev-Ran 2014 [104]
Anxiety Disorders 1.3 to 1.68 S Kedzior 2014 [105]
Table 4. Reported adverse events associated with cannabis, synthetic cannabi-
noids and cannabis mimetics.
System Disorders References
Respiratory system [106,107]
Dyspnea
Pneumonia
Pleural effusion
Lower respiratory tracts infection
Pulmonary embolism
Gastrointestinal
system
[108]
Vomiting*
Diarrhea
Gastroenteritis
Abdominal pain
Duodenal ulcer
Constipation
Nausea*
Dry mouth*
Nervous system [109113]
Relapse of multiple sclerosis
Convulsion
Cerebrovascular disorders
Dizziness*
adolescent Deficiencies in memory, attention,
Inhibition and verbal fluency, decline in
IQ score
[114]
Drug addiction
Psychiatric system [103,104]
Agitation/anxiety/depression*
Self-harm/suicide ideation
Psycosis/schizophrenia
Paranoia/allucinations
Renal and urinary
system
[115]
Acute kidney injury
Haematurya/proteinuria
Cardiovascular
system
[116]
Tachycardia*
Congestive heart failure
Immune system [117]
Increase incidences of common infectious
diseases and viral infections
Pregnancy [118]
Intra uterine growth retardation
Congenital birth defects
Effects on sperm
and testicular
health
[119]
A significant decline in sperm count,
concentration and motility. Increase in
abnormal sperm morphology in who
smoked cannabis
*depending on the age of the user
Table 5. Possible interactions between cannabis and other pharmacological
products.
DRUGS INTERACTIONS RESULTS
Olanzapine Delirium
SSRIs Mania
Cocaine Tachycardia/Euphoria
Ethanol Increase THC
Warfarin Increase INR
Sildenafil Myocardial infarction
Tricyclics Delirium/Tachycardia
Barbitures CSN Depression
1028 P. SARZI-PUTTINI ET AL.
preliminary laboratory findings support cannabinoid treatment
for rheumatic diseases, there is still a scarcity of clinical trials and,
although some have been conducted in the field of RA, OA and
FM, their small sample sizes and the inconsistencies of their
findings prevent the drawing of definite conclusions and the
formulation of recommendations. Furthermore, there seems to
be a gap between the encouraging results obtained in animal
models and the inconclusive results of clinical studies.
7. Expert opinion
The possible therapeutic properties of cannabis have been
known since ancient times. Over time, use as a medicine has
been abandoned in favor of that for recreational purposes;
only with the isolation in 1960s of D9 Tetraidrocannabinol,
interest in medical cannabis has rekindled so much that the
hottest question currently for clinicians is if it is possible to
recommend cannabis as a new therapeutic option.
First of all, its important to bring order to the confusion of
terms between herbal cannabis, medical cannabis and canna-
binoids. The term cannabiscovers very different uses, includ-
ing both illegal drugs and cannabis for medical use. The fact
that low-cannabinol oils and extracts are proposed as nutri-
tional supplements contributes to the confusion.
The term medical cannabis(or medical marijuana) should
refer to the entire unprocessed marijuana plant or extracts for
medical reasons and should be distinguished from cannabinoids
which are natural, synthetic, semi-synthetic or plant-derived com-
pounds, but always chemically composed such as 9-tetrahydro-
cannabinol (THC), cannabidiol (CBD), nabilone and Dronabinol.
An additive effect is shown by medical cannabis compared
to pure extracts; no single active component of cannabis has
this effect but the pharmacological action is probably related
to the synergistic action of the different components (entou-
rage effect). Cannabis can be consumed in a variety of differ-
ent ways and although the most commonly used are smoking,
vaporization and ingestion, we do not agree and contraindi-
cate smoking and vaporization of medical cannabis because of
the high variance of bioavailability and short-term suprather-
apeutic plasma levels .
The lack of clinical evidence on the long-term side effects
of cannabis use should be emphasized.
The few existing clinical studies refer to the short term
effects and the use of cannabis for recreational purposes.
The most frequently reported adverse events were nervous
system disorders, psychiatric disorders, gastrointestinal disor-
ders and vascular and cardiac disorders.
The current insufficient evidences do not allow recom-
mending any cannabinoid preparation for rheumatology
patients; so cannabis and cannabis-based medicines are not
yet prescribed among health professionals and there are still
conflicting positions in the professional association.
The growing public opinion, which is pushing toward the
legalization of the use of cannabis in chronic pain and various
rheumatic conditions, makes it necessary to have educational
programs, extended basic and clinical research that spread the
correct knowledge into the mechanisms and clinical utility of
cannabis and derivatives and their long-term side effects and
allow a correct, rational and conscientious prescription from the
medical community.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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... [172] Endocannabinoids 2-AG, AEA, PEA and, OEA Suppressed production of pro-inflammatory cytokines and matrix metalloproteinases, reduced bone resorption. [186,187,192] fibroblasts differentiate into fibroblast-like synoviocytes (FLS) via transforming epigenetic modifications [61]. Both FLS and chondrocytes can secrete reactive oxygen species (ROS) and other free radicals, which may be involved in signal transduction in multiple metabolic pathways. ...
... However, CB2 may also mediate pro-inflammatory responses by increasing IL-1β levels and re-pression of CB2, reducing inflammatory signalling in RASF. The ECS plays an intricate role in the pathogenesis of RA, representing a valuable target for future investigation [185,186]. ...
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... On contrary, it was found to exhibit significant anticonvulsant, sedative and other pharmacological activities by interacting with the effects of THC. Studies have shown that CBN decreases heart rate, intestinal mobility and inhibits platelet aggregation [96,[98][99][100][101]. ...
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... Cannabinoids may be useful in the management of FM due to their effects on pain and associated symptoms [67]. Recent studies indicate a possible clinical advantage and safety of adjunctive medical cannabis treatment in adult FM patients [68]. ...
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This chapter reviews the indications and evidence for the use of cannabinoids for pain in light of the complexity of their clinical use. The human body hosts a vast and intricate innate cannabinoid system, comprising both receptors and ligands, and enzymes that synthesize and degrade the ligands. Cannabis is widely used to treat chronic pain either by clinicians’ prescriptions or through self‐treatment. Compared to other pain medications, cannabis is considered relatively safe and life‐threatening adverse events of cannabinoids are rare. Headache is a common side effect of cannabinoids. Proper patient selection is a key to safe and efficient use of cannabinoids, along with intelligent choice of appropriate cannabinoid preparations, open and accurate communication and gradual titration of low doses of cannabinoids. Prior to the prescription of cannabinoids, it is advisable to query the available databases for possible drug‐drug interaction. Cannabinoids have the potential to become a powerful therapeutic tool for pain and its accompanying symptoms.
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BACKGROUND: This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain. OBJECTIVES: To assess the efficacy, tolerability, and safety of cannabis-based medicines (herbal, plant-derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults. SEARCH METHODS: In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles. SELECTION CRITERIA: We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health-related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta-analysis was undertaken using a random-effects model. We assessed the quality of evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.Primary outcomesCannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate-quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence).Secondary outcomesCannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low-quality evidence).We found no information about long-term risks in the studies analysed.Subgroup analysesWe are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence). AUTHORS' CONCLUSIONS: The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.
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As medical use of cannabis is increasingly legalized worldwide, a better understanding of the medical and hazardous effects of this drug is imperative. The pain associated with rheumatic diseases is considered a prevalent indication for medicinal cannabis in various countries. Thus far, preliminary clinical trials have explored the effects of cannabis on rheumatoid arthritis, osteoarthritis and fibromyalgia; preliminary evidence has also found an association between the cannabinoid system and other rheumatic conditions, including systemic sclerosis and juvenile idiopathic arthritis. The potential medicinal effects of cannabis could be attributable to its influence on the immune system, as it exerts an immunomodulatory effect on various immune cells, including T cells, B cells and macrophages. However, the available evidence is not yet sufficient to support the recommendation of cannabinoid treatment for rheumatic diseases.
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The endocannabinoid (eCB) system plays a key role in many physiological and pathological conditions and its dysregulation has been described in several rheumatological and autoimmune diseases. Yet, its possible alteration in systemic lupus erythematosus (SLE) has never been investigated. Here, we aimed filling this gap in plasma and peripheral blood mononuclear cells (PBMCs) of patients with SLE and age- and sex- matched healthy subjects (HS). Liquid chromatography-mass spectrometry quantitation of eCB levels highlighted that plasma levels of 2-arachidonoylglycerol (2-AG) were significantly increased in SLE patients compared to HS (p = 0.0059), and among SLE patients, highest 2-AG levels were associated with a lower disease activity. No differences were found in N-arachidonoylethanolamine (AEA) and its congeners N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) concentrations between the two groups. Moreover, gene expression analysis of metabolic enzymes and receptor targets of eCBs and investigation of functional activity and protein expression of selected components of eCB system disclosed a deranged 2-AG metabolism in patients with SLE. Indeed, expression and functional activity of 2-AG biosynthetic enzyme DAGL were selectively enhanced in PBMCs of SLE patients compared to HS. In conclusion, our results demonstrate, for the first time, an alteration of eCB system in SLE patients. They represents the first step toward the understanding of the role of eCB system in SLE that likely suggest DAGL and 2-AG as potential biomarkers of SLE in easily accessible blood samples. Our data provides proof-of-concept to the development of cannabis-based medicine as immune-modulating agents.