Cannabinoids and autoimmune diseases: A systematic review
Valeria Katchan, Paula David, Yehuda Shoenfeld
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doi: 10.1016/j.autrev.2016.02.008
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Autoimmunity Reviews

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3 February 2016

Please cite this article as: Katchan Valeria, David Paula, Shoenfeld Yehuda, Cannabinoids and autoimmune diseases: A systematic review, Autoimmunity Reviews (2016), doi:
10.1016/j.autrev.2016.02.008

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CANNABINOIDS AND AUTOIMMUNE DISEASES: A SYSTEMATIC REVIEW

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Valeria Katchan MD 1,3 ; Paula David 2,3, ; Yehuda Shoenfeld MD, FRCP, MaACR 3, 4

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1 Departamento de Medicina Interna, Hospital La Paz, Madrid, Spain

2 Faculdade de Cincias Mdicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro,

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Brasil

3 Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer,

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Israel

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4 Sackler Faculty of Medicine, Tel-Aviv University, Israel;

Corresponding author: Yehuda Shoenfeld MD, FRCP (Hon.), MaCR, Head of Zabludowicz

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Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. E-

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mail address: shoenfel@post.tau.ac.il

Tel: 972-3-5308070, 972-52-6669020

Key Words: Cannabinoids, Endocannabinoid system, Autoimmune Diseases, Immunosuppression, Tetrahydrocannabinol (THC), Type 1 Diabetes, Neuropathic Pain, Fibromyalgia, Inflammatory Bowel Disease, Multiple Sclerosis, Scleroderma, Rheumatoid Arthritis
ABSTRACT

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Cannabinoids have shown to have a variety effects on body systems. Through CB1 and CB2 receptors, amongst other, they exert an effect by modulating neurotransmitter and cytokine release.
Current research in the role of cannabinoids in the immune system shows that they possess im-

munosuppressive properties. They can inhibit proliferation of leucocytes, induce apoptosis of T

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cells and macrophages and reduce secretion of pro-inflammatory cytokines. In mice models,

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they are effective in reducing inflammation in arthritis, multiple sclerosis, have a positive effect

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on neuropathic pain and in type 1 diabetes mellitus. They are effective as treatment for fibromyalgia and have shown to have anti-fibrotic effect in scleroderma. Studies in human models
are scarce and not conclusive and more research is required in this field. Cannabinoids can be

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therefore promising immunosuppressive and anti-fibrotic agents in the therapy of autoimmune

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disorders.

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1. Introduction
Cannabinoids are diverse chemical compounds that can bind to receptors of our endocannabinoid

system. Cannabinoids can be endocannabinoids, when produced by our own body, phytocanna-

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binoids, present naturally in the plant Cannabis sativa [1,2], and synthetic cannabinoids. The

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most well-known cannabinoid is 9-tetrahydrocannabinol (9-THC), the main constituent of

cannabis. Nabilone, a synthetic analogue of 9-THC has been licensed for medical use [2]. En-

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docannabinoid system and the physiological effects of cannabinoids have been widely studied in
the past decades. Cannabinoids are believed to have immunomodulatory effects and therefore
their potential role as an autoimmune/inflammatory treatment has been extensively investigated.

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Herewith, we revise the properties and the effects of cannabinoids on autoimmune disorders

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known so far.

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2. The Endocannabinoid System

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2.1 Cannabinoid Receptor Agonists

Cannabinoids receptor agonists are very heterogeneous and can be divided into four groups ac-

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cording to the difference in their chemical structure. These are classical, non-classical, aminoalkylindole and eicosanoid compounds groups. [1,2]
Briefly, the classical group consists of phytocannabinoids (9-THC, cannabinol) and their synthetic analogues. The eicosanoid group are mostly endocannabinoids, produced by our own cells.
These are arachidonoylethanolamide (anandamide),O-arachidonoylethanolamine (virodhamine),
2-arachidonoyl glycerol and 2-arachidonyl glyceryl ) and several synthetic analogues of anandamide. The two other groups, non-classical and aminoalkylindole consist of synthetic cannabinoids. (See Table 1)
Cannabinoids act on the two main receptors of the endocannabinoid system, CB1 and CB2 receptors. Every endocannabinoid agonist has a different affinity for the receptors. For example,

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9-THC has a higher affinity for CB1 receptor and the phytocannabinoid cannabinol is an agonist without marked CB1/CB2 selectivity. (Fig 1)

2.2 Cannabinoid RECEPTORS

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2.21 CB1 and CB2 receptors

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There are two types of cannabinoid receptor that have been mostly identified and studied. These
are CB1 and CB2 receptors. They belong to a class of cell membrane receptors under the G pro-

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tein-coupled receptor superfamily and consist of seven transmembrane spanning domains. The
effect of binding is variable from partial agonism, functional selectivity to inverse agonism and

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all play important roles in determining the cellular response to specific cannabinoid receptor li-

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gands.

2.22 Mechanism of action of CB1 and CB2 receptors

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Both, CB1 and CB2 receptors produce their effects through heterotrimeric Gi/o proteins coupled

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to them. CB1 receptor activated exhibits its effects mainly through activation of G alpha i/o. Biding of CB1 to its agonist leads to inhibition of the production of adenylate cyclase enzyme. Con-

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sequently, the binding between CB1 and its ligands decrease the intracellular cAMP levels and
an increase the mitogen-activated protein kinase (MAP kinase). In some cases CB1 receptor activation may be coupled to Gs proteins, which stimulate adenylate cyclase. cAMP. [3,4]
CB1 and CB2 receptors are also coupled to a variety of ion channels in the cell membrane,
which are the positively influenced inwardly rectifying potassium channels (=Kir or IRK)(-) and
the calcium channels. These channels are activated when there is a cAMP dependent interaction
between the receptor and the molecules such as protein kinase A (PKA), protein kinase C(PKC),
Raf-1, ERK, JNK, p38, c-fos, c-jun, and others. [5]
In case of CB1, activation can produce a subsequent decrease of Ca2+ entry into the cell, without
involvement of cAMP, which is the requirement for neurotransmitter release. The overall effect

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is a decrease in the neurotransmitter release. CB1 receptor is therefore a pre-synaptic receptor
that modulates neurotransmitter release when activated in a dose-dependent manner [6].
CB1 and CB2 cannabinoid receptors also act to regulate the phosphorylation and activation of

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different members of the family of mitogen- activated- protein kinases (MAPKs), including
extracellular signal regulated kinase-1 and -2 (ERK1/2), p38 MAPK and c-Jun N-terminal kinase

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and apoptosis as well as glucose metabolism [6].

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(JNK). MAPK, in turn controls gene expression related to cell proliferation, motility, adhesion

CB1 and CB 2 receptors produce their effects through the stimulation by their agonists.

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(endogenous/ exogenous/ synthetic). After release, agonist molecules are rapidly deactivated by
uptake into cells and metabolized. Metabolism of anandamide and 2-AG occurs by either enzymatic hydrolysis with a help of fatty acid amide hydrolase enzyme (FAAH) [7,8] or other meta-

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bolic processes, including hydrolysis of 2-AG by monoglyceride lipase [9].

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The mechanism is summarized in Figure 2.

2.23 Distribution of cannabinoid receptors:

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CB1 receptors are expressed by central and peripheral neurons and also by some non-neuronal

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cells [1,2, 10]. Within the central nervous system, the distribution pattern of CB1 receptors is
heterogeneous and can be related to their function. CB1 receptors are densely distributed in cerebral cortex, hippocampus, caudate-putamen, substantia nigra pars reticulata, globus pallidus,
entopeduncular nucleus and cerebellum, as well as in other areas of the brain and spinal cord.
They process or modulate nociceptive information.

Distribution within the central nervous

system might be related to CB1 receptor agonists' ability to impair cognition and memory, to alter the control of motor function and to produce anti nociception [1, 10, 11,12 ].
Some CB1 receptors are located on central and peripheral nerve terminal, where they modulate
the release of excitatory and inhibitory neurotransmitters when activated [1, 2].CB2 receptors are
expressed mainly on immune cells [ 2, 10] and have a role in immunomodulation.

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Both, CB1 and CB2 receptors share the ability to modulate the release of chemical messengers.
By acting on CB1 receptors, cannabinoids interact with a multitude neurotransmitters at the CNS
and can modulate their release. [13]. CB2 control the release of inflammatory cytokines, regulat-

ing the immune system.

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2.3 Other cannabinoid receptors of the endocannabinoid system. Cannabinoid Non- CB1 Non-

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CB2 receptors

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2.3a Vanilloid receptors:

One of the non CB1/CB2 receptors described, with binding capacity to cannabinoids is TRVP1
receptor, also called capsaicin receptor. It is a non-selective cation channel that is present on

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sensory neurons in tissues such as skin, heart, blood vessels and lung. TRPV1 receptors are
found mainly in the nociceptive neurons of the peripheral nervous system, but they have also

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been described in many other tissues, including the central nervous system. TRPV1 is involved

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in the transmission and modulation of pain (nociception) [35,14,15] through sensory primary afferent and perivascular neurons. It has been shown that activation of TRPV1 by the endogenous

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cannabinoid anandamide leads to a release of substance P (SP) and of calcitonin gene-related

(CGRP), which have allogenic and local vasodilatory and pro-inflammatory effects, as well as

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beneficial actions such as cardio protection and anti-hypertensive effects. [16-22]

2.3b Non-CB1, Non-CB2, non- Vanilloid receptors.
It has been shown by successive experiments that many biological effects of the cannabinoids
are not reversed by CB1 / CB2 antagonists. Additional receptor pathways, including the peroxisome proliferator-activated receptors (PPARs), G-protein receptor 55 (GPR55) as well as nicotine, 5-HT3 and adenosine A2A receptors, have been involved in cannabinoid signal transduction. [23,24]
2.3c Allosteric sites for cannabinoids
Apart from different receptors, there is an evidence for the presence of allosteric sites for anandamide and other cannabinoids on several non-cannabinoid receptors [1,26 ]. These are 5-HT2

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receptors [27], 5-HT3 receptors [28,29,30,31], 1-adrenoceptors, M1 and M4 muscarinic receptors [32] and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GLUA1 and
GLUA3 glutamate receptors [33,34]The biological consequences of occupation of the proposed

allosteric sites on 5-HT2 receptors (by HU-210) and on M1 and M4 receptors (by anandamide,

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methanandamide and SR141716A) have not been determined yet.[1]

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2.4 Effects of cannabinoids on body systems. (See Table 2)

The effects of cannabinoids include analgesia, muscle relaxation, immunosuppression, antiinflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-

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emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. [36]

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2.4a Cannabinoids and the Central Nervous System (CNS):

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Cannabinoids interact with different neurotransmitters and neuromodulators [36- 39], among
them acetylcholine, dopamine, -aminobutyric acid (GABA), histamine, serotonin, glutamate,

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norepinephrine, prostaglandins and opioid peptides. Some effects of THC of the body can be
explained by these interactions. For example, tachycardia and hypo salivation with dry mouth

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[40,41] are mediated by the effects of THC on the release and turn-over of acetylcholine [40].
The antiemetic properties of cannabinoid are explained by interactions with serotonin [42]. Therapeutic effects in movement and spastic disorders could be ascribed in part to interactions with
GABAergic, glutamergic and dopaminergic transmitters systems [43,44].
Neuroprotective cannabinoid effects observed in animal studies are based on inhibition of excessive glutamate production, inhibition of calcium influx into cells and the anti-oxidant properties
which reduce damage caused by oxygen radicals and modulation of vascular tone [36, 45-47].
The use of cannabinoids as a treatment of stroke and brain injury is therefore being investigated.

2.4b Cannabinoids and the circulatory system:

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Stimulating the endocannabinoid system with THC leads to tachycardia [36,48] and increased
cardiac output, cardiac labor and oxygen demand [49]. It can also produce peripheral vasodilation and orthostatic hypotension [50,51] mediated by central inhibition of the sympathicus sys-

tem, by activation of CB1 receptors [54]. It has been shown that endocannabinoids can be syn-

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thesized by vascular endothelium, circulating macrophages and platelets [52] and the subsequent

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activation of vascular cannabinoid CB1 receptors can decrease vascular resistance in the coro-

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nary arteries and the brain [53]

2.4c Cannabinoids, appetite and eating

Endocannabinoids control appetite though leptin signaling pathway in the hypothalamus [55].

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Leptin downregulates food intake by upregulating appetite-reducing neuropeptides and downregulating appetite-stimulating factors. . In animal model, reduced levels of leptin were associated

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with elevated levels of endocannabinoids in the hypothalamus [55]. Cannabinoid antagonists

have been tried to treat obesity but a selective loss of positive emotional memory in healthy vo-

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lunteers was noted. [62]

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Rest of the effects on osteoarticular, digestive, reproductive, ocular and immune system are re-

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sumed in Table 2.

3. Endocannabinoid System and its potential role in medicine

Several studies about cannabinoids system and their possible actions in medical purposes have
been done in the last decades. Cannabinoids have multiple physiological effects. Hence, modulation of endocannabinoids system, with agonists and antagonists, have been broadly studied as
potential novel treatments for different diseases. For example, Anandamide could increase food
intake in rats [63] and has been approved to increase weight in cancer and HIV+ patients, while
the antagonist SR-141716A inhibits the intake of food [64, 65, 66], being a potential anti-obesity
treatment, acting probably in the CB1 receptor in the hypothalamus [67]. They were already
shown to be effective in many medical conditions listed in Table 3.

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4. How cannabinoids are consumed
Cannabinoids can be consumed in several ways. However, the pharmacokinetics of 9-THC is
different in each manner [68]. Possible forms of administration are listed in Table 4, with their

advantages and limitations to being used for medical purposes. The most well-known and used

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5. Cannabinoids and the immune system

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way of administration of cannabinoids is inhaling.

Immune cells express CB1 and CB2 receptors and can synthesize, secrete, transport and catabolize cannabinoids [69-73]. The expression of cannabinoids receptors is different in each immune

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cell. They are expressed, from the most abundant to the less extensive, on B cells, natural killer
cells (NK), monocytes, neutrophils, CD8 leucocytes and CD4 leucocytes. The level of expres-

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sion also depends on the immune stimulation and on the activation state of the cell [74].

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In mice, deficiency in the Fatty Acid Amide Hydrolase (FAAH), anandamide-catabolizing enzyme, elevates the levels of anandanamide (an endocannabinoid) in the CNS and periphery. In-

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creased levels of anandamide attenuate inflammatory responses, suggesting that the endocanna-

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binoids are physiologically involved in dampening the immune system [75-77].

The evidences that endocannabinoid system has probably immunomodulatory effects generated
the theory that exogenous cannabinoids might also have immunosuppressive effects, being a potential novel therapy to autoimmune and inflammatory disease. Since then, several studies about
this association have been published. [71, 78-80].
9-THC can modulate Th1/Th2 balance by enhancing Th2 and suppressing Th1 immune responses [81-84]. Although, the psychoactive effects of 9-THC limit its potential as a therapy.
Cannabidiol, on the other hand, has low affinity for the CB1 and CB2 receptors, resulting in no
psychoactive effects [85,86]. Besides, Cannabidiol is well tolerated without side effects when
chronically administered to humans [87, 88].

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Cannabinoids were shown, in vivo and in vitro, to exert their immunosuppressive properties
through 4 main pathways: induction of apoptosis, inhibition of cell proliferation, inhibition of

cytokines and chemokines production and induction of regulatory T cells (T regs) [89].

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5.1 Cannabinoids induce apoptosis

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Anandamide was shown to induce apoptosis in mitogen-induced T and B human lymphocytes,

human neuroblastoma CHP100 cells and lymphoma U937 cells, depending on the dose [90, 91].

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It was also observed that 9-THC can trigger apoptosis in murine macrophages and T cells,
through regulation of BCl2 and caspase activity [92].

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However, there is no demonstration of cannabinoids inducing apoptosis in vivo, perhaps because

through phagocytes [89]

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apoptosis detection in vivo is difficult since the apoptotic cells are rapidly and efficiently cleared

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9-THC injection in C57BL/6 mice (10 mg/kg body weight) was demonstrated to decrease the

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cellularity in the spleen and thymus, affecting several cell populations such as T cells, B cells
and macrophages. [93]. When administered at a lower concentration (10 M), 9-THC only in-

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duced AnnexinV + cells, which is indicative of early apoptotic cells, but at higher concentrations
(20 M), the splenocytes had both AnnexinV and PI positive, which represent late apoptotic as
well as necrotic cells.
9-THC may affect more intensively naive lymphocyte than activated lymphocytes. Levels of
apoptosis were shown to be greater in cultures treated only with THC, when compared to the
cultures that contained 9-THC and mitogen [93]. In the same study, it was noticed that activated lymphocytes can down-regulate the expression of CB2, decreasing their sensitivity to 9THC.

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Administration of CB2 antagonists block 9-THC-induced apoptosis in lymphocytes and thymocytes, while CB1 antagonists failed to show a significant effect, what suggest that 9-THC

induces apoptosis via CB2 receptors [93].

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Cannabidiol was also demonstrated to induce apoptosis in a time-and-dose dependent manner on

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CD4+ and CD8+ T cell populations, on murine thymocytes and on EL-4 cells. Cannabidiol lead
to apoptosis by producing reactive oxygen species (ROS) and activating caspase 8 and caspase 3.

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[94]
5.2 Cannabinoids inhibit immune cell proliferation

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While low doses of 9-THC stimulate T cell, high doses of 9-THC inhibited responses to LPS,
T cell mitogens and anti-CD3 antibody in both human and mice in vitro studies [95]. This bi-

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phasic role of cannabinoids has also been shown on B cells: a study demonstrated increased B

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cell proliferation in response to 9-THC [96], and, on the other hand, another study showed de-

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creased B cells response to LPS after cannabinoid treatment [95].

9-THC could suppress immune functions and increase susceptibility to infections in experi-

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mental models. The precise mechanism by which 9-THC suppress the immunity is still unclear.
The inhibition of lymphocytes proliferation in those cultures might be induced through direct
effects on immune cells, and not in CB1 and CB2, once it still observed in presence of CB1 and
CB2 antagonists [97]. 9-THC can also decreased proliferation of thymocytes. This effect was
shown to happen by inhibiting the calcium stabilization within the cell [98]. Low doses of anandamide were also able to inhibited proliferation of T and B lymphocytes after mitogen stimulation [90].
5.3 Cannabinoids inhibit cytokine and chemokine production and inflammatory cells migration
Cannabidiol inhibits IL1, IL12, TNF alfa and interferon-gama (INF-g) cytokine release by peripheral blood mononuclear cells, and enhances production of the Th2-associated cytokines, IL-4

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and IL-10 [99]. Cannabidiol can also reduce prostaglandin E2 and tissue cyclooxygenase (COX)
activity [P61]. 9-THC also changes destructive TH1 immunity to protective TH2 immunity, but

less effectively than Cannabidiol [70, 100-104]

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Cannabinoids can regulate monocytes differentiation to M1 or M2 macrophage phenotypes, as

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well as their ability to produce cytokines, chemokines and other immune mediators [105-112].
The responses to cannabinoids in the immune system are different in people who usually use

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consume cannabis and in the ones that are not. Phytocannabinoids can inhibit monocyte migration in individuals exposed to cannabis more than twice a week (non-nave), while they do not

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affect subjects that never tried or that were not exposed in the past 3 years (nave) [113]. In this
study, endocannabinoids and synthetic cannabinoids had no effect in both groups. The authors

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also demonstrated that monocytes isolated from cannabis non-nave subjects expressed fourfold
higher amounts of CB1 receptor mRNA than cannabis nave subjects, whereas CB2 receptor

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mRNA remained unchanged between the two cohorts. These results show that the sensitivity of

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monocytes isolated from non-nave subjects to phytocannabinoids correlates with enhanced expression of CB1 receptors.

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9-THC was also shown to have immunosuppressive effects in Legionella pneumophila (Lp)
infected dendritic cells. When the dendritic cells were pretreated with 9-THC, the immunization potential of Lp-loaded cells in mice was suppressed. 9-THC suppressed IL-12p40 production by the dendritic cells and inhibited expression of maturation markers such as MHCII, CD86,
and CD40 [114].
5.4 Cannabinoids induct regulatory T cells
9-THC can increase the number of Foxp3+ Treg cells. In a ConA-induced hepatitis model, 9THC was able to alleviate liver damage, it was not only by increasing levels of apoptosis in activated T cells, but also by inducing Treg cells to inhibit the cytokines induced in vivo by ConA

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[89]. More studies are still needed, but it suggests that Treg cells, unlike other T cells, may be
resistant to apoptosis induced by 9-THC and may suppress the activation of T cells that even-

tually escape from apoptosis. [89, 115]

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5.5 Other cannabinoids immunomodulatory effects

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Cannabis and certain cannabinoid receptor ligands have the ability to suppress serum immunoglobulin (Ig) levels [69, 70, 116]. 9-THC reduces B cell numbers while decreases IgG and IgM

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levels [116]. Although, this effect is controversial: some authors believe that there are no
changes in B cell levels [117].

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Cannabinoid receptor ligands can suppress spreading and phagocytosis, cytolysis, cytokine production, and antigen presentation in mouse peritoneal macrophages [118-124]. They also sup-

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press, in vivo and in vitro, NK cells and cytotoxic effector functions. [125-127].

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5.6 Cannabinoids as pro-inflammatory molecules?

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Despite all these data, some studies suggest that cannabinoids could also have pro-inflammatory
effects. [128,129]: promoting allergic reactions [130]; releasing inflammatory mediators through

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CB1 receptors in mast cells [129], increasing B cell proliferation [95].

The key to understand the role of cannabinoids in immunomodulation is to stress that their effects depend on the type of cannabinoid, on the type of cells that they are acting on and on the
doses administrated. In optimal concentrations, cannabinoids can induce apoptosis in immune
cells, alleviating inflammatory responses and protecting the host from acute and chronic inflammation. Thus, they can be beneficial when an immune suppression is necessary. Additional research is still needed to validate these studies in humans through clinical trials.
The effects of the three main cannabinoids that could be beneficial to autoimmune diseases are
summarized in Fig 4.

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6. Effects of cannabinoids in autoimmune disorders
6.1 Cannabinoids in Multiple Sclerosis (MS)
MS is a chronic neuroinflammatory autoimmune demyelinating disease of the human central

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nervous system, mediated by T lymphocytes. The inflammatory process leads to BBB disruption, causing swelling, activation of macrophages, and further production of cytokines and cyto-

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toxic proteins such as metalloproteinases.

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In mice model of MS (Experimental Autoimmune Encephalomyelitis (EAE)) it has been shown

that CB1 receptors play an important role in the control of neuroinflammation. Mice deficient in
CB1 tolerate inflammatory and exitotoxic insults poorly and develop substantial neurodegenera-

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tion following immune attack [131].

THC has been reported to inhibit neurodegeneration in the EAE model by reducing inflammato-

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ry cytokines and to reduce the associated induced elevated level of glutamate in cerebrospinal

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fluid [132]. Glutamate, the major excitatory neurotransmitter in the cerebral cortex, has been implicated in neurodegenerative disease when present at high levels.

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Studies in the CB1 knockout mice showed greater susceptibility to neurofilament damage, caspase 3 activation as well as greater dephosphorylation of a neurofilament H epitope, considered

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as a marker of axonal damage during chronic relapsing EAE. [133] Collectively, the data suggested that signaling through CB1 conferred neuroprotection during EAE.
Studies have also shown that CB1 receptor activation exhibited down-regulatory responses in
the motor regions of CNS system where they were expressed and could explain the improvement in motor symptoms such as spasticity, tremor, and ataxia of mice and human models
treated with CB1 agonists.[134] Rolipram, an inhibitor of type IV phosphodiesterase that suppresses EAE in different species, has been found to attenuate clinical decline, reduce motor inhibition, and normalize CB1 gene expression in the basal ganglia of EAE rats [135]. EAE rats also
have been reported to exhibit changes in endocannabinoid levels presenting decreased levels of

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anandamide and 2-AG in motor related regions such as the striatum and midbrain as well as in
other brain regions. [135].
CB2-selective agonists such as RWJ400065 have not shown to inhibit spasticity.

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However , CB2-deficient T lymphocytes in the CNS during EAE exhibit reduced levels of apoptosis, a higher rate of proliferation, and increased production of inflammatory cytokines resulting

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in severe clinical disease. In addition, selective glial expression of both, CB1, CB2, and FAAH

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has been reported as associated with MS, supporting a role for the endocannabinoid system in
the pathogenesis and/ or evolution of this disease [136]

Endogenous cannabinoid, anandamide plays an important role in controlling the inflammatory

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process during the course of MS progression. It was demonstrated that treatment with the selective anandamide uptake inhibitor UCM707 during established disease resulted in a significant

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improvement in motor function. UCM707 was able to reduce microglial activation, diminish

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MHC class II antigen expression, decrease cellular infiltrates in the spinal cord, and decrease the
production of the pro-inflammatory cytokines TNF-, IL-1, and IL-6. The endocannabinoid

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system is highly activated during CNS inflammation and anandamide protects neurons from inflammatory damage through a CB1/CB2-mediated rapid induction of microglial mitogen-

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activated protein kinase phosphatase-1 (mkp-1) [137].

Studies in humans are scarce. Recently the results of a clinical trial have been published where
the effect of (9)-tetrahydrocannabinol was tried in 498 patients with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.06.5. No differences
were found in the rate of progression of MS in both groups although lower than expected progression rates might have affected the ability to detect clinical change. [138]
Nevertheless, there is sufficient data to suggest symptomatic improvement when cannabinoid
treatment is used in MS patients. Studies done in patients with MS with the aim to see the effect
of THC on spasticity and pain proved long-term symptomatic improvement of spasticity and relief of pain. [139-141]

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6.2 Cannabinoids in Rheumatoid Arthritis.

Joint diseases, inflammatory and degenerative, all share a pathological feature which is the loss

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of articular cartilage. In osteoarthritis and rheumatoid arthritis (RA), there is an increased cartilage breakdown. It is induced by an increased production of inflammatory cytokines, particularly

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IL-1 and tumor necrosis factor (TNF) produced by the articular chondrocytes or cells of the syn-

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ovium [142]. The overall result is an increase in metalloproteinases (MMPs) particularly MMP3 and MMP-13, which are responsible for cartilage destruction.
Cannabinoids were shown to have anti-inflammatory effects and reduce to joint damage in ani-

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mal models of arthritis [143-145] According to in vitro studies, cannabinoids reduce cytokine
production by RA fibroblasts as well as the release of matrix metalloproteinases (MMPs) from

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fibroblast-like synovial cells [146-148]. Cannabinoids have also shown to reduce interleukin 1

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(IL-1) induced proteoglycan and collagen degradation in bovine cartilage, thus reducing cartilage
extracellular matrix (ECM) breakdown [149].

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Studies have been performed with synthetic cannabinoid WIN-55,212-2 mesylate (WIN-55). It is
an agonist of CB1, CB2 receptors and also has an ability to activate other receptors including

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peroxisome proliferator activated receptors alpha and gamma (PPARa and g) [150-152]. It was
proved that WIN-55 can reduce the gene and protein expression of MMP-3 and MMP-13 in the
presence of IL-1b, suggesting that cannabinoids may have potential in terms of arthritis therapy.
It also significantly reduces the gene expression of TIMP-1 and TIMP-2 tissue inhibitors of matrix metalloproteinases to below basal levels. [153]
Similar results were obtained with a selective CB2R agonist (HU-308) in vitro. Pre-treatment
with HU-308 inhibited IL-1-induced proliferation of cultured RA fibroblast-like synoviocytes.
The agonist also decreased the production of proinflammatory cytokines (IL-6 specifically) and
of matrix metalloproteinases that are thought to be involved in cartilage erosion (MMP3 and
MMP13.) In another study non-psychoactive cannabinoid ajulemic acid (AJA) reduced MMP-1,

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MMP-3 and MMP-9 release from fibroblast like synovial cells stimulated with IL-1a and TNFa
[148]. In vivo, AJA has also been shown to reduce the severity of adjuvant-induced arthritis
[144]. When a novel synthetic cannabinoid acid, Hebrew University 320 (HU-320) was admi-

nistered to a mouse model of arthritis, inhibition of mouse macrophages TNF production was

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observed. The authors also noticed reduction of reactive oxygen intermediates and suppression

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of the rise in serum TNF level following endotoxin challenge. [153]

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All these data suggests that cannabinoids have anti-inflammatory properties and should be considered as a treatment for inflammatory arthritis. There are no studies in humans up to date on
the use of cannabinoids reducing inflammation in RA and further studies are needed to prove

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that.

There are however, studies which have shown that cannabinoids are efficient in the treatment of

ED

pain associated with RA. There is evidence that endocannabinoid system plays an important role
in the peripheral regulation of nociception [154,155]. CB1R present on nociceptor terminals may

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mediate the anti-nociceptive and anti-inflammatory actions of locally produced N-arachidonoyl

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ethanolamine through its inhibitory influence on the release of excitatory neuropeptides [155]
CB1R and CB2R are also expressed in the dorsal root ganglia, and their stimulation at this level

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also decreases nociceptive transmission [156,157]. At the central level, the endocannabinoid
system controls nociception through CB1R located at spinal and supraspinal levels [158] Pharmacological studies have suggested a peripheral endocannabinoid basal activity that modulates
nociceptor activity in osteoarthritic joints [159]. CB1R and CB2R mRNA and protein, were
found in synovial biopsies deriving from total knee arthroplasty of advanced osteoarthritis and
rheumatoid arthritis patients [160] Both, anandamide (AEA) and 2-arachidonoylglycerol (2-AG)
were detected in the synovial fluid of these patients, but not in healthy volunteers, providing further evidence for a functional endocannabinoid system in osteoarthritic joints [160] Spinal cord
levels of AEA, 2-AG and their synthesizing enzymes were also increased in the rat model of os-

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teoarthritis [161] All these findings provide evidence for both peripheral and central adaptive
changes involving the endocannabinoid system during osteoarthritis.
Studies on human models are scarce and contradictory. A recent review article on the effect of

cannabinoid nabiximol on chronic pain in rheumatic diseases shows that there is a low-quality

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evidence suggesting that cannabinoids may be associated with improvements in pain and sleep

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quality in RA. Measures of morning pain at rest, sleep quality and a global disease activity score

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showed improvement, but measures of pain intensity were unchanged [162]. However, Savitex (
dronabiol) is sometimes used to reduce pain in inflammatory joint disease- [163]
6.3 Cannabinoids in Scleroderma:

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Cannabinoid receptors CB1 and CB2 were found to be over-expressed in scleroderma fibroblasts
compared with healthy fibroblasts. A study was carried out to see the effect of WIN55,212-2,

ED

CB1 CB2 agonist on the production of collagen. It was demonstrated that WIN55,212-2 induced

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inhibition of type I collagen as well as procollagen type I PIP supernatant levels, which was also
associated with changes in skin fibrosis [164]. The reduction in type 1 collagen production was

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accompanied by a decrease in levels of growth factors involved in the fibrotic process, TGF beta and its downstream mediator CTGF. There was also an inhibition of fibroblast trans diffe-

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rentiation and inhibition of the over-expressed IL-6 in scleroderma cultures, known to be involved in scleroderma pathogenesis [165].
The agonist WIN55,212-2 also significantly increased the number of scleroderma fibroblasts
undergoing apoptosis. These observations are consistent with the anti-proliferative effect of cannabinoids. [166]. No toxicity of WIN55,212-2 on cell cultures was found. However, the antifibrogenic effect of WIN55,212-2 did not seem to be mediated by the classic cannabinoid receptors CB1 and CB2 and it was proposed that ERK signaling pathways may be involved. [167]
Further studies have shown that additional receptor pathways, including the transient receptor
potential vannilloid type-1 (TRPV1), the peroxisome proliferator-activated receptors (PPARs),
G-protein receptor 55 (GPR55) as well as nicotine, 5-HT3 and adenosine A2A receptors are in-

ACCEPTED MANUSCRIPT
volved in cannabinoid signal transduction.[168,169] Oral administration of Ajulemic Acid
(AjA), a non-psychoactive synthetic analogue of tetrahydrocannabinol able to bind the peroxisome proliferator-activated receptor- (PPAR-) prevented the development of skin fibrosis, and

reduced skin thickness nearly to control levels. At the biological level it produced dose depen-

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dent reduction of procollagen and 5 TGF- [170]. According to these observations, the stimula-

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tion of peroxisome proliferator-activated receptor- (PPAR-) could have an anti-fibrotic effect

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and cannabinoids should be studied as a potential anti fibrotic treatment.

6.4 Cannabis in Type 1 Diabetes

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In type 1 diabetes mellitus, the insulin-pancreatic b-cells are destroyed, most probably, mediated
by CD4 Th1 and CD8 T lymphocytes [171,172]. During insulitis, the initial lesion of this dis-

ED

ease, leukocytes, especially lymphocytes, surround and infiltrate the islets [173].
Cannabidiol treatment of 6 to 12 week-old Non-Obese-Diabetes (NOD) mice was shown to sig-

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nificantly reduce the incidence of diabetes (from 86% in non-treated control mice to 30% in

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mice treated with cannabidiol). The plasma levels of INF-gama and TNF-alfa were reduced too,
as well as other TH1 cytokines. The production of IL4 and IL10 (TH2 cytokines), on the other

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hand, was increased. When histological examination of the pancreatic islets was done, cannabidiol treated mice revealed significantly reduced insulitis. Therefore, cannabinoids can inhibit or
at least delay destructive insulitis and TH1 associated cytokine in NOD mice. [99]
Despite the fact that cannabinoid could prevent diabetes type 1 in NOD young mice, it was not
demonstrated to ameliorate diabetes after onset or around onset time. Thus, the same authors repeated the experiment with cannabidiol treatment, this time with 11 to 14 week-old NOD mice.
They observed amelioration of diabetes manifestations: while the untreated and the emulsifiertreated group had 86% and 100%, respectively, of diabetes incidence at the end of the treatment;
the group treated with cannabidiol had only 32%. Histological examination of the pancreas of
cannabidiol treated mice revealed more intact islets than in the controls [174].

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It was suggested that cannabidiol could have a role in prevention of human type 1 diabetes.
However, it depends on the mechanism of the anti-autoimmune properties of this molecule. The
main issue is to determine if it is a non-specific immunosuppressive agent or if it deviates Th1 to

the response. If it is a non-specific immunosuppression mechanism, it requires lifelong treat-

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ment. Log-term therapy causes substantial potential risks, including possible enhanced suscepti-

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bility to opportunistic infection and increased risk of malignancy. Diabetes also has longstanding

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consequences, but they can be reduced with intensive insulin therapy aimed at normalizing glucose levels [175], what makes cannabinoid therapy need to be carefully evaluated before using in
humans. On the other hand, if cannabidiol is causing the deviation from Th1 to Th2, it could be

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used to prevent diabetes in early on-set patients, before complete beta-cells destruction, and
maybe in high risk individuals. Once the autoimmune response is deviated from a destructive

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Th1 response to a protective Th2 response, cannabidiol therapy is no longer required, eliminat-

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ing the concern regarding long-term safety issues. [99]

Cytokines released by macrophages have a critical immunomodulatory role in skewing the im-

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mune response to either Th1 or Th2 [176]. Administration of IL-12 to macrophage-depleted

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NOD mice is known to initiate the disease [177]. Cannabidiol was shown to significantly reduce
macrophage IL-12 production. [174] By reducing IL12, it induces TH2 differentiation and also
reduces INF-g production. INF-g, that potentiates IL12 effects, activates cytotoxic T cells and
stimulates macrophages to produce TNF-alfa, IL1 and IL6, besides nitrogen free radicals. Those
molecules are associated with beta cells destruction [178-180]. Therefore, cannabidiol suppression of macrophage IL-12 production could inhibit Th1-mediated autoimmunity [99].
At onset of diabetes most patients have approximately 10% functional beta cells, evidenced by
residual c-peptide secretion. Approximately 50% of patients diagnosed with type 1 diabetes will
enter a honeymoon remission phase of diabetes and remain insulin independent within the first
year of diagnosis [99]. These patients have sufficient residual beta cells to maintain normoglycemia and insulin independence, so they could be candidates for immunomodulation therapy.

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Studies are still needed to prove if a Th1/Th2 shift actually happens in humans, and if it occurs,
it really provides long-term protection from disease without other interventions.

6.5. Cannabis and Inflammatory Bowel Diseases

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Cannabis has been widely used to cure disturbances and inflammation of the bowel. The me-

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chanisms involved are still unclear, but probably include peripheral actions on CB1 and CB2 and

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may also include central actions [181].

Many animal experiments studies of cannabinoids possible therapy in colitis have been done in
the last decade. Most of them showed reduced inflammation with cannabinoid agonists, while

MA

cannabinoid antagonists or cannabinoid receptor knockout increased inflammation [182-189].

ED

Recently, studies with human colitis patients are underway.

Cannabinoids receptors are differentially expressed in human IBD, indicating a cannabinoid reg-

PT

ulatory role in the disease progress [104, 190, 192].

CE

Anandamide and its synthesizing enzyme are decreased in Ulcerative Colitis (UC), and the expression of CB2 receptors and of enzymes responsible for synthesis and degradation of 2-

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Arachidonoylglycerol are increased [193]. It suggests that cannabinoids can ameliorate the IBD.
There are CB1 and CB2 receptors located at the colonic epithelium, so cannabinoids might enhance epithelial wound closure in the colon [194]. The activation of CB2 also leads to apoptosis
and decreased proliferation of T cells in colitis, and diminishes the recruitment of neutrophils, T
cells and macrophages to the inflamed colon [195].
The endocannabinoid system can also control gut motility and secretion, by CB receptors located
in the enteric nervous system [192, 196]. These CB1 receptors can protect the bowels from the
hyper stimulation that happen during IBD. By this mechanism, THC may improve IBD symptoms, mainly diarrhea, besides controlling the inflammation [196-198].

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The possible central effect would be the reduction in pain sensation and relief of nausea, induced
by stimulation on CB1 present in the central nervous system. This theory is supported by the fact
that one study with peripherally restricted CB1 and CB2 agonist was too weak to improve colitis

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[199].

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In a prospective placebo-controlled study with 21 Crohn Disease patients [200], cannabis induced clinical remission in 50% of patients. 80% of the participants had nonresponse or intoler-

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ance to antiTNF-alfa. Although, the improvement was only symptomatic, with no induction of
remission comparing to placebo. When patients discontinued the cannabis therapy, relapses were
noticed in 2 weeks. Other cohort study of patients with IBD using cannabis [201] also reported

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that the patients perceive that it improved abdominal pain. Patients with UC, in particular, re-

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ported cannabis to improve diarrhea.

In another observational study [202], this time with in 30 patients with Crohns disease, medical

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cannabis was associated with improvement in disease activity and reduction in the use of other

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medications was reported.

Usually, 25% to 38% of operated Crohns disease patients require a second operation within 5

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years [203], but in a retrospective cohort study [204] only 2 of 15 patients (13%) who had surgery before cannabis consumption required surgery while consuming cannabis. Studies are still
needed, but this one suggested that the use of cannabis reduces the need for surgery.
Some patients with UC and CD also use cannabis to enhance appetite [205]. In a study of 13
patients using cannabis for 3 months, a statistically significant increase in the subjects weight
was observed [206]. They also presented improvement in the disease activity index, perception
of general health status, and ability to perform daily activities.

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There is evidence that cannabinoids treatment could have beneficial effects on IBD. However,
further research is required before it can be established which cannabinoid to use, in what dose

and in which administration mode [202].

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6.6. Cannabis in neuropathic pain

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Neuropathic pain is a disease of peripheral or central nervous system. It happens when peripheral
nerves, spinal cord, or brain are injured or the sensory system functions in the wrong way. There

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are many causes such as underlying pathological process (e.g., neuropathy) and catastrophic injury (e.g., stroke or spinal cord injury) [207]. The treatment for neuropathic pain is a difficult

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field, because in randomized clinical trials, less than half of patients report clinically meaningful
pain relief from pharmacotherapy, most of them, just partial relief [208]. Because of that, and

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due to the studied anti-inflammatory potential of cannabis, a lot of studies about cannabinoid

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therapy to neuropathic pain have been performed [209].

Chronic pain is associated with the worst quality of life as compared with other chronic diseases

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such as chronic heart, lung or kidney disease, and what's more, is associated with a higher risk of
suicide [210, 211]. A systematic review about cannabis in chronic non-cancer pain, especially in

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neuropathic pain, [212] selected 18 randomized control trials demonstrating a modest analgesic
effect of cannabinoids in chronic pain.
A recent qualitative systematic review [213] stated that new safe and effective agonists at the
cannabinoid receptors may dissociate therapeutic effects from psychotropic effects. For example,
1,1Dimethylheptyl-8-tetrahydrocannabinol-11-oic acid (CT-3) is a synthetic analog of THC11-oic acid, one of the endogenous transformation products of THC. It was shown to be a potent
anti-inflammatory, analgesic and antiallodynic agent with no psychoactive properties in preclinical studies [214].

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The exact neurobiological mechanism of action of cannabinoids is still unclear. Some studies
claim that they work by binding to CB1 and in the intracellular peroxisome proliferator
activated receptor (PPAR), which is directly associated to anti-inflammatory and antitumor

effects [213-215]. Other studies suggest that there is an inhibition of eicosanoid synthesis and

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down-regulation of COX2 [216].

In order to examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in

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humans, a randomized placebo-controlled double-blind crossover trial was preformed [217].

There were 28 patients with examination consistent with chronic neuropathic pain for at least 6
months with hyperalgesia and allodynia. They analyzed visual analog scale (VAS) and verbal

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rating scale scores for pain. It was observed that the VAS values in the CT-3 sequence, measured
3 hours after intake of study drug, differed significantly from those in the placeboCT-3 se-

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quence (11.54 [14.16] vs 9.86 [21.43]; P = .02). Although 8 hours after intake of the drug, the

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pain scale differences between groups were less marked.

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In two different trials, patients with HIV peripheral neuropathy in cannabinoid therapy showed
reduction in the pain (46-52%) compared to 18-24% in the placebo groups [218, 219]. This type

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of pain is notoriously resistant to other treatments normally used for neuropathic pain, which
emphasize the importance of these study. [220]
Another group [221] made a human experimental model of neuropathic pain using intradermal
injection of capsaicin in healthy volunteers and tested the efficacy of different doses of THC as a
therapy. Low dose cigarettes (2% THC) had no analgesic value, while high dose (8% THC) cigarettes were associated with reports of an increase in pain. On the other hand, the medium dose of
cannabis cigarettes (4% THC) produced significant analgesia.
A randomized double-blind placebo-controlled trial published in 2014, [207] compared medium
dose (3.53% THC) to low dose (1.29% THC) cannabis, to see if the analgesia was sufficient in
the low doses. The purpose was that if it as effective as the medium dose, it should be used pre-

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ferentially, to avoid side effects. Both provided statistically significant 30% reductions in pain
intensity when compared to placebo.

In a crossover trial with 23 patients with post-traumatic or post-surgical neuropathic pain [222],

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it was given 4 different doses of THC to the patients (0%, 2.5%, 6% and 9.4%) for four 14-days

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periods. It was inhale through a pipe three times a day for the first 5 days, followed by 9 days
washout period, in each cycle. The pain intensity was measured daily by a numeric rating scale.

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They also analyzed the effects on mood, sleep and quality of life. The average daily pain measured was lower on the pre-specified primary contrast of 9.4% to 0% (5.4 to 6.1 respectively). Individuals who received 9.4% THC demonstrated improved ability to fall asleep and quality of

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sleep, when compared to the 0% THC group. There was no differences in mood or in quality of

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life.

All those studies showed that modulating the cannabinoid system can help patients with neuro-

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pathic pain, not only by relieving their pain, but also by improving their sleeping skills. Further

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long-term safety and efficacy are still needed.

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6.7 Fibromyalgia:

FM is characterized by chronic widespread pain and elevated response to pressure which is perceived as pain. Other symptoms include tiredness, morning stiffness, sleep and emotional disturbances as well as cognitive dysfunction [223]. The pathophysiology of the disorder is not
known. Several mechanisms have been proposed including central sensitization, suppression of
descending inhibitory pathways, excessive activity of glial cells, abnormalities of neurotransmitter release as well as abnormal response to stress. [224]. Currently, the treatment is based on the
relief of symptoms but poor results are achieved. The participation of the endocannabinoid system in multiple physiological functions such as pain modulation, stress response system, neuroendocrine regulation and cognitive functions amongst others, is well known [225]... It was
suggested that clinical endocannabinoid deficiency may underlie the hyperalgesic tender muscle

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points of this condition and play an important part in etiopathology of myofascial pain syndrome
fibromyalgia [226,227].
Some studies provide data that cannabinoids can prove to be an effective treatment of fibromyal-

gia symptoms. One retrospective study of fibromyalgia affected patients who were chronic users

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of cannabis, analyzed the effect of smoked, oral and combined cannabis on symptoms and the

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quality of life. A significant reduction of pain and stiffness, enhancement of relaxation, and an

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increase in somnolence and feeling of wellbeing were observed in cannabis users. Furthermore,
mental health component summary score was significantly higher (p=0.05) in cannabis users

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than in non-users [228].

Some data suggests the beneficial effect on sleep in fibromyalgia patients. Nabilone had shown
to be effective in improving sleep in patients with FM and was well tolerated. Low-dose nabi-

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lone given once daily at bedtime may be considered as an alternative to amitriptyline treatment.

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[229]

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7. Adverse Effects of Cannabis

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Due to the extend distribution of its receptors, cannabis are known to have many side effects.
The most important ones are listed in Table 5.
In a systematic study [230], 8371 adverse events related to medical cannabinoid use were reported, 4779 of which were reported in 23 randomized controlled trials and 3592 in 8 observational studies.
Patients in cannabinoid therapy presented twice the incidence of severe adverse events than control groups. Respiratory (16.5%), gastrointestinal (16.5%) and nervous system disorders (15.2%)
were the most frequently reported categories of serious adverse events among those assigned to
cannabinoids, whereas nervous system disorders (30%) were the most frequently reported among

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controls. The events considered severe side effect were: dyspnea, pneumonia, pleural effusion,
lower respiratory tract infection and pulmonary embolism; vomiting, diarrhea, gastroenteritis,

abdominal pain, constipation, duodenal ulcer; relapse of multiple sclerosis, convulsions.

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15 deaths were also reported among cannabinoid users against 3 deaths in the control group, al-

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though these results did not prove to be statistically significant. [230]

The incidence rate of non-serious adverse events was significantly higher among subjects as-

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signed to cannabinoid therapy than among controls, dizziness being the most frequent nonserious adverse event among cannabinoid-exposed participants.

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8. Conclusion

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Cannabinoids are potent inflammatory modulators and in several animal studies, in vivo and in
vitro, they have shown to have an immunosuppressive effect.

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However, human studies are still few.

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Models of multiple sclerosis, rheumatoid arthritis, scleroderma and type 1 diabetes evidenced

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clinical improvement as well as biochemical and/or histological anti-inflammatory changes. Inflammatory bowel disease, neuropathic pain and fibromyalgia were studied in human subjects
and improvement of pain, positive effect on sleep and better quality of life were noted. In ulcerative colitis there were less diarrhea symptoms after cannabinoid administration.
Certain types of cannabinoids, like cannabidiol, have low affinity to CB1 and CB2. Others, such
as certain synthetic cannabinoids, have higher affinity for CB2 receptor. However, they do produce immunomodulatory effect without being psychoactive. Therefore, they have a potential in
research, as a possible therapy for autoimmune diseases
Nevertheless, cannabis are known to have many adverse effects, including memory impairment.
THC is related to a decrease in gray matter volume and lower IQ levels. It can also trigger some

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psychiatric disorders. Because of the THC stimulation of dopaminergic pathways involved in
drug addiction, it can lead to dependence and drug abuse.

Further studies are required. How cannabinoids should be consumed, their optimal doses and

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which type of cannabinoids would be more effective, with fewer side effects still remain as ques-

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tions to be answered.

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Table 1. Cannabinoids receptor agonists groups and its components. [1,2]
Classical

Non-Classical

Aminoalkylin-

Eicosanoid

noids:

cyclic analogues

512

9-THC that

THC

lack a pyran ring:

THC

Canna

binol

AC

PT

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noids:

HU210

Virodhamine

2-arachidonoyl glycerol( 2-AG)

Synthetic analogues of anandamide:

R-(+)methanandamide

CP55
244

Anandamide

Arachidonyl-2-

HU-

chloroethylamide

308

(ACEA)

Arachidonylcyclo-

JWH-

propylamide (AC-

133

PA)

L-

O-689

759633

O-1812

L759656

CP47
497

Synthetic cannabi-

Endocannabinoids:

P5594

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9-

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of

WIN5

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Bicyclic and tri-

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Phytocannabi-

dole

L-

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nantra-

dol

Desace-

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tyl-l-

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nantra-

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ED

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dol.

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Table 2: Effects of Cannabinoids in the Human Body

Effect

Reference

Body System

Anti-emetic; neuroprotective, nociception. Se-

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dating. Simpaticomimethic

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CNS

Tachycardia, increased cardiac output

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Circulatory

[40]

[49,50,51,53,54]

Vasodilation and orthostatic hypotension

Stimulation by leptin inhibition

Osteoarticular

Bone formation

Gastrointestinal

Inhibition of motility and gastric secretion

PT

ED

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Appetite and eating

AC

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Reproductive system

Minor changes in hormone levels, no effect when

[55]

[56]

[57,58]
[51,59]

tolerance is reached.
Decrease in sperm count without functional impairment

Ocular

Vasodilation. Descrease intraocular pressure

[60,61]

Immune system

Inmunosupression, immunomodulation

[69-73]

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Table 3: Medical conditions in which cannabinoids were shown to be effective.

Improve pain

Post-operative and trauma

Improve pain

Chronic pain in cancer

231, 232

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pain

References

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Effect

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Medical condition

Chemotherapy induced nausea Improve symptoms of nausea

and vomiting

Cancer cachexia and HIV

Improve appetite and

234-239

240-243

ED

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and vomiting

233

increasing weight in

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disease

Spasticity, movement

Improve symptoms

244-246

Improve symptoms, pain and

191, 247

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disorders and dystonia

Ggastro-intestinal conditions

(gastric ulcers, irritable bowel increase life quality

syndrome, ulcerative colitis,
Crohns disease, secretory
diarrhea, paralytic ileus and
gastroesophageal reflux
disease)

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Table 4: How cannabinoids can be consumed: advantages and limitations.

Limitations

References

Cutaneous absorption

No need to eat or

Takes too long to act.

by adhesives

inhale

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applications.

No need to inhale.

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Oral absorption

Onset of action after

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30-60 minutes.

Peak of action 2-3

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hours after ingestions

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248

No clinical

impregnated by herbs

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Administration form Advantadges

Increased
bioavailability by
presence of food in
the stomach and
gastric acid partial
destruction.
Psychoactive effects
due to conversion of
9-THC to 11hydroxy-THC in the
liver (9-10 times more
psychoactive than 9THC)

249, 250

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Limitations

References

Intravenous

No need to eat or

Needs a vehicle to

248, 251

administration (bolus

inhale.

permits aqueous

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Fast absorption (goes

administration due to
cannabis low water

directly to the

solubility.

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systemic circulation)

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or infusion)

Administration form Advantadges

Rectal administration

No need to eat or

(suppositories)

inhale.

251

Peak of action in 20-

Needs combustion

252

administration -

30 minutes after

(can lead to lung

smoking (cigarettes,

smoking

lesions).

High intensity and

Plasma levels

short duration of

depending on volume

action (2-3 hours)

and respiratory rate.

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Irregular absorption

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Fast absorption (goes

directly to the

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systemic circulation)

AC

CE

Inhaling

pipes)

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Limitations

References

Inhaling

No need for

Plasma levels

248, 253

administration -

combustion

depending on volume

dispositive that boils

the cannabis herbs,

as intravenous

creating a vapor that

can be inhale without

high lipossolubility, it
crosses rapidly the

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combustion)

alveolar membrane
reaching the blood

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through pulmonary

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PT

capillaries)

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and respiratory rate.

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injection (due to its

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Peak of action as fast

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vaporizer (portable

Administration form Advantadges

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Table 5: Side effects of cannabinoids in each system.
Examples:

References

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ED

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Effects

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Effects

Examples:

References

Neuropsychiatric effects

Dysphoric mood alterations

230, 254-262

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like anxiety, panic.

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Psychosis

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Sedation

Impaired global and

prospective memory, verbal

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immediate and delayed recall

and visual recognition.

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Convulsion

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CE

PT

Lower IQ (depending on age at

onset)
Decrease in gray matter
volume in the medial temporal
cortex, temporal pole,
parahippocampal gyrus, left
insula, and orbitofrontal cortex
Increased appetite.
Drug Addiction

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Effects

Examples:

References

Immune system effects

Increase incidences of

230, 259, 260, 263-270

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common infectious diseases

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Increase susceptibility to viral

infections such as herpes

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simplex virus, Listeria

monocytogenes,

Staphylococcus albus,

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Treponema pallidum and

ED

Legionella pneumophila
Allergies to cannabis (rare):

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PT

contact urticaria and rhino

AC

Vascular system

conjunctivitis

Syncope
Transient ischemic attack
Stroke

259,260

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Effects

Examples:

References

Respiratory system

Chronic respiratory irritation

230, 267

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Inflammatory changes in

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respiratory tract

Suppression in responsiveness

Dyspnea

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to infectious disease

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Pneumonia

PT

ED

Pleura effusion

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Gastrointestinal system

Vomiting
Nausea
Diarrhea
Gastroenteritis
Abdominal pain
constipation
Duodenal ulcer

230

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ED

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Figure 1: Cannabinoids agonists and antagonists

The table resumes the most important cannabinoid agonists and antagonists. AEA and 2-AG are
endogenous agonists and D9-tetrahydrocannabinol (D9-THC), the main psychoactive cannabis
component is an exogenous agonist. Together with synthetic derivatives (HU 210, HU 308,CP
55,940, etc.), they are the compounds most frequently used as pharmacologic tools.

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Fig. 2. CB1 CB2 signaling.

Both CB1 and CB2 cannabinoid receptors are associated with G proteins. Activation of these
leads to inhibition of adenylyl cyclase activity and activation of the different MAPK cascades. In
addition, the CB1 cannabinoid receptor negatively regulates voltage-gated Ca2+ channels and
positively regulates inwardly rectifying K+ channels. CB1 receptor can also induce elevation of
intracellular free Ca2+ through activation of phospholipase C (PLC). Cannabinoid-mediated inhibition of protein kinase A ( PKA) leads to inhibition of gene expression through a decrease in
cAMP . It also results in activation of MAPK cascades related to cell survival/apoptosis. These
signaling pathways are directly related to the variety of functions regulated by cannabinoid receptors.

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Fig 3. Action of cannabinoids at the presynaptic terminal.

Cannabinoid agonists such as THC, 2- Ag and AEA bind to CB1 receptors, causing change
in intracellular Ca2+ and K+ level. This in turn leads to neurotransmitter release inhibition at the presynaptic neuron. Cannabinoids are destroyed at the postsynaptic neuron by
FAAH enzyme and the metabolites are recycled.

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Figure 4: Benefit effects of cannabinoids in autoimmune diseases.

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