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Cannabinoid Receptor 2: Potential Role in Immunomodulation and Neuroinflammation.

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J Neuroimmune Pharmacol. Author manuscript; available in PMC 2014 Jun 1.
Published in final edited form as:
PMCID: PMC3663904

Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review


An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB1, CB2) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer’s disease to name a few), mainly mediated by CB2 activation. Development of CB2 agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB2 activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection.

Keywords: cannabinoid receptor, endocannabinoids, medical marijuana, HIV-1, monocyte/macrophage, endothelial cells


Pub MedThe cannabinoids are a group of terpenophenolic compounds present in the marijuana plant, Cannabis sativa. At present, three general types of cannabinoids have been identified: phytocannabinoids present uniquely in the cannabis plant, endogenous cannabinoids produced in humans and animals, and synthetic cannabinoids generated in a laboratory (Sarfaraz et al., 2008). It is worth noting that Cannabis sativa produces over 80 cannabinoids (Console-Bram et al., 2012). The broader definition of cannabinoids refers to a group of substances that are structurally related to Δ9-tetrahydrocannabinol (Δ9-THC) or that bind to cannabinoid receptors. The chemical definition includes a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the non-classical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, quinolines and arylsulphonamides (Woelkart et al., 2008Console-Bram et al., 2012), and additional compounds that do not fall into these standard classes, but bind to cannabinoid receptors (CB). Multifaceted effects of marijuana can be singled out aiming at evaluation of the potential medical value of marijuana and cannabinoids in specific human diseases, with minimal undesired side effects.

Nomenclature of cannabinoid receptors (CB)

There are two well-characterized CB with distinctly different physiological properties. The psychoactive effects of cannabinoids are associated with the CB1 receptor; the CB2 receptor mainly mediates anti-inflammatory and immunomodulatory actions (Miller and Stella, 2008).


Cannabinoid receptor 1 (CB1) was discovered by Devane et al. in 1988 (Devane et al., 1988). CB1cDNA was cloned by Matsuda et al. (Matsuda et al., 1990) from rats using a homology approach to G-protein-coupled receptors (GPCR). Subsequently, CB1 receptors have been found in other vertebrates as well. The genes for mouse, rat and human CB1 receptors (CNR1) are located on chromosomes 4, 5 and 6, respectively. The CB1 receptor is widely distributed throughout the brain regions, especially the frontal cortex, the limbic system, including the hippocampus and amygdala, sensory and motor areas, hypothalamus, pons and medulla (Ashton et al., 2007Ashton and Moore, 2011). Human CB1 shares 94% amino acid sequence identity with rodent CB1 (Anday and Mercier, 2005). In addition to full-length CB1 receptor, two splice variants, human CB1a and human CB1b, have been described. Both splice variants have altered ligand binding and activation properties compared to full length CB1, and are expressed at very low levels in different tissues (Ryberg et al., 2005). In contrast, another group demonstrated no significant differences between the three variants (full-length and two splice-variants) in pharmacological characteristics, such as binding affinity, functional potency, and efficacy of several CB1 agonists (Xiao et al., 2008). The functional significance of different human cannabinoid CB1 receptor variants remains to be clarified.

The majority of high CB1-expressing cells are GABAergic (gamma-aminobutyric acid) neurons belonging mainly to the cholecystokinin-positive and parvalbumin-negative type of interneurons (basket cells) and, to a less extent, to the mid-proximal dendritic inhibitory interneurons. Only a fraction of low CB1-expressing cells is GABAergic. In the hippocampus, amygdala and entorhinal cortex areas, CB1 mRNA is present at low but significant levels in many non-GABAergic neuronal cells (Marsicano and Lutz, 1999).


The second cannabinoid receptor (CB2) was isolated from human myeloid cells in 1992 (Munro et al., 1993). Soon afterwards, CB2 was identified in other species, such as mouse, rat, bovine and zebra fish. The CB2 gene is located on chromosome 1 and 4 in humans and mice, respectively. Unlike the mouse CB2 gene, which is intron-less, the human gene has been reported to have two splice variants (Liu et al., 2009). The longer variant human CB2a, comprised of exon 1a, exon 1b and exon 3, is mostly expressed in testis (about 100-fold more compared to spleen or leukocytes). It is also detected in various regions of the brain (Liu et al., 2009). The shorter variant, human CB2b, consisting of exon 2 and exon 3, is expressed mostly in the spleen and leukocytes, 100-and 30-fold higher, respectively, when compared to CB2b expression in the brain (Liu et al., 2009). Immune cells express high levels of CB2 and there is a hierarchy of CB2 expression within the immune system (B cells > natural killer cells > monocytes > neutrophils > CD8 lymphocytes > CD4 lymphocytes)(Nunez et al., 2004Yao and Mackie, 2009). The level of expression is dependent on the activation state of the cell and the type of stimuli. Stimulation of splenocytes with LPS leads to CB2 mRNA down- regulation, whereas CD40 co-stimulation results in CB2 mRNA up-regulation (Lee et al., 2001). CB2 receptor sequences are less conserved throughout evolution compared to CB1 receptors. CB2 and CB1 receptors share about 44% identity in humans at the level of amino acids (Liu et al., 2009Console-Bram et al., 2012). Humans and mice share about 82% identity in amino acid sequence of CB2 (Anday and Mercier, 2005), whereas mice and rat share 93% identity. Human, rat and mouse sequences diverge at the C-terminus. The mouse protein is 13 amino acids shorter, while the rat protein is 50 amino acids longer than the human (Console-Bram et al., 2012). Diversity in CB2 sequences between species can possibly explain differential effects of CB2 agonists in human and rodent models (Figure 1).

Figure 1

Multiple alignment and homology of human and mouse CB1 and CB2 receptors. Sequence alignment was performed using ClustalW tool ( The following symbols denote the degree of conservation observed in each column: 

Structural similarities and differences of CB2 and CB1

Cannabinoid receptors are integral membrane proteins whose amino acid sequences are characterized by seven hydrophobic segments containing -helical patterns. CBs belong to α group of rhodopsin-like seven-transmembrane (7TM) GPCRs (Palczewski et al., 2000). CBs share the structural characteristics of other GPCRs: an extracellular N-terminus that is glycosylated, seven transmembrane α-helixes with extracellular and intracellular loops, and an intracellular C-terminus (Ahn et al., 2009). While CB1 and CB2 are encoded by different genes, they exhibit 44% amino acid identity throughout the whole protein (Figure 1). Since CBs are intrinsic membrane proteins, they are difficult to crystallize for X-ray study. Although their crystal structures are not available, homology models built by using bovine rhodopsin as a template, along with resolution NMR and computer modeling, have revealed that the most important differences between CB1 and CB2 with respect to their interaction with the surrounding lipid environment are located in theTM7 juxtamembrane domain (Dainese et al., 2008). CB1 presents a hydrophobic surface at the helix I-helix VII interface that is suitable for a specific interaction with cholesterol and palmitic acid, whereas CB2 displays a negatively charged region within TM7, which is rather unfavorable for any interaction with lipids. Arg302 in CB2 TM7 (homologous to Arg401 in CB1) is not available for any interaction with cholesterol or with G-proteins (Xie and Chen, 2005). Despite the ability to be activated by the same endocannabinoids and trigger the same signaling pathways, CB2 is independent of membrane cholesterol content (Bari et al., 2006).

In every TM domain, there are residues that have been probed for their importance in ligand binding or signal transduction. CB2 helix III is in contact with the other helixes and plays an important role in the regulation of cannabinoid activities (Xie et al., 2003). CB2 Ser112 has been shown to be crucial for recognition of several cannabinoid ligands (based on mutagenesis studies)(Tao et al., 1999). The homologous residue in the CB1 TM3 is Gly195 (Xie et al., 2003). Unlike the CB1 receptor, in which Lys192 plays an important role for the binding of most cannabinoid ligands, the homologous residue Lys109 in CB2 TM3 does not appear to be a key residue (Tao et al., 1999Xie et al., 2003). Mutagenesis studies indicate that the TM4 domain in CB2 plays a more important role for the recognition of the cannabinoid ligand that in CB1. The CB2-selective antagonist, SR144528, completely fails to antagonize the CB2 in S161A or S165A mutants, which is explained by existence of alanines in the homologous two sites of TM4 of the CB1 receptor (Xie et al., 2003). To date, studies of the CB2 have been limited by the lack of a three dimensional structure, leaving many unanswered questions about interactions at the molecular level with its ligands as well as the nature of the receptor active site(s) (Xie and Chen, 2005). Knowledge of the three-dimensional structure of CB2 should greatly aid in the rational design of specific CB2 ligands possessing therapeutic activities, but devoid of undesirable side effects. The dissimilarities between the two receptors could be exploited to design CB2-specific ligands in the future.

Medical marijuana

Medical marijuana refers to the parts of the cannabis plant used as a physician-recommended form of herbal therapy or as medicine (synthetic analogs of cannabinoids). In the US recently, use of medical marijuana has surged in the 16 states and the District of Columbia that permit its use. The cannabis plant has a long history of use as a medicine dating back to 2737 B.C. (Ben Amar, 2006). Cannabis sativa contains over 80 different chemical constituents (Molina et al., 2011Console-Bram et al., 2012). There are three phytocannabinoids (Figure 2): THC, cannabidiol (CBD) and cannabinol (CBN). THC is a primary component of cannabis, responsible for the psychoactive effects of the plant; it has mild analgesic and antioxidant activities (Hampson et al., 1998Molina et al., 2010). CBD represents up to 40% of the extract of medicinal cannabis. It has been shown to relieve cough, congestion and nausea, convulsion, inflammation and anxiety, and has been shown to be effective in treating multiple sclerosis (MS), anxiety attacks and schizophrenia (Crippa and Zuardi, 2006Zuardi et al., 2006aZuardi et al., 2006bKogan et al., 2007Mechoulam et al., 2007Lakhan and Rowland, 2009). CBN is a breakdown product of THC and acts as a weak agonist of CB1 and CB2 because of lower affinity than THC toward receptors (Mahadevan et al., 2000).

Figure 2

Prototypical structures of natural and synthetic cannabinoids.

There are several medications (plant extracts or synthetic cannabinoid analogues of THC alone or in combination with CBD) that have been approved for medicinal use. Nabilone® was approved in the US and Canada in 1985 as an anti-nausea treatment for patients undergoing cancer chemotherapy (Todaro, 2012). Sativex® was approved in Canada and the UK for treatment of neuropathic pain in MS and pain associated with cancer (Russo et al., 2007Sastre-Garriga et al., 2007). Sativex® has been also approved for MS-associated spasticity in many countries, such as New Zealand, UK, Austria, Czech Republic, Denmark, Germany, Sweden, Israel, Italy and Spain (Leussink et al., 2012). In the majority of cases, administration of cannabinoids (natural or synthetic analogs) results in improvement of symptoms of MS, especially spasticity, muscle pain, tremors and bladder control. However, there were differences in the actions of orally administered versus inhaled cannabinoids, probably due to variable absorption of orally administered cannabinoids (Maurer et al., 1990Russo et al., 2007). Several studies have been done on the pharmacokinetics of cannabinoids during different routes of drug administration. Smoking, the major route, provides a rapid and efficient method for drug delivery from the lungs to the brain, contributing to its abuse potential. The number, duration and spacing of the puffs, as well as holding time and inhalation volumes, greatly affect the degree of exposure (Heishman et al., 1989Azorlosa et al., 1992). Synthetic THC, Dronabinol (Marinol®), is usually taken orally, but may also be administered rectally. In addition, abuse is being common by the oral route. Absorption is slower when cannabinoids are ingested, with lower and delayed peak THC concentrations (Law et al., 1984Huestis, 2007). To prevent first-pass metabolism by the liver, Sativex® is administered sublingually, via the oromucosal route. The oromucosal form of administration has the advantage that the first-pass effects are reduced and, compared to smoking, the maximum plasma THC levels are lower and increase more slowly (Karst et al., 2010Leussink et al., 2012). Because MS is considered to be a relapsing chronic inflammatory disease of the CNS, beneficial anti-inflammatory effects of cannabinoids would provide much needed MS symptom relief. Clinical benefits for the use of cannabinoids in MS patients were also supported by studies in animal models of MS (Baker et al., 2001Pryce and Baker, 2005Mestre et al., 2009).

CB1 antagonists (AM251 and SR141716A) lead to changes in efflux of noradrenaline and dopamine in various brain regions, leading to antidepressant effects (Tzavara et al., 2003Witkin et al., 2005). These studies suggest the possibility of use of cannabinoids in the treatment of mood disorders, such as depression, anxiety, manic depression and posttraumatic stress (Ashton and Moore, 2011).

Marinol® (Dronabinol) was approved by the US and Canada in 1985 for patients undergoing cancer chemotherapy to relieve nausea associated with treatment. In 1992, it was approved for treatment of anorexia associated with AIDS-related weight loss (Dejesus et al., 2007Todaro, 2012).

Cannabinoids are increasingly being used for treatment of migraine headaches in patients that are not responding to the serotonin 1D agonist, sumatripan (Krymchantowski and Jevoux Cda, 2007). Dronabinol has been shown to inhibit the 5-HT3 receptor involved in emetic and pain responses (Fan, 1995). A patent has been filed for the use of Dronabiniol for treatment of migraines (Barbato, 2007). Canasol® is used for reduction of intraocular pressure in glaucoma (Crandall et al., 2007). Cannabinoid compounds applied topically show hypotensive and neuroprotective effects in mice and monkeys (Williams et al., 2007Yazulla, 2008). In 1992, the FDA approved the use of Dronabinol to stimulate appetite in AIDS patients suffering from wasting syndrome. This triggered further interest in the development of cannabinoid antagonists that would reduce appetite. Rimonabant has been shown to suppress appetite, producing reduction in body weight (Pi-Sunyer et al., 2006). Dronabinol has been shown to be a potent drug for treatment of HIV-associated sensory neuropathy, the most common peripheral nerve disorder complicating HIV-1 infection (Abrams et al., 2007).

Synthetic cannabinoid agonists

Synthetic cannabinoids are functionally similar to THC, the active part of cannabis. Like THC, they bind to the same cannabinoid receptors in the brain and other organs as the endogenous ligands, anandamide and 2-arachidonylglycerol, which interact with both CB1 and CB2 receptors. More correctly designated as cannabinoid receptor agonists, synthetic cannabinoid agonists were developed over the past forty years as therapeutic agents, often for the treatment of pain. However, it proved difficult to separate their desired properties from unwanted psychoactive effects.

Although often referred to simply as synthetic cannabinoids, many of the substances are not structurally related to the so-called “classical” cannabinoids, i.e., compounds like THC, based on dibenzopyran. The cannabinoid receptor agonists form a diverse group, but most are lipid soluble, non-polar, and consist of 22 to 26 carbon atoms; they would therefore be expected to volatilize readily when smoked. A common structural feature is a side-chain, where optimal activity requires more than four and up to nine saturated carbon atoms. The first figure shows the structure of THC, while the others show examples of synthetic cannabinoid receptor agonists, all of which have been found in “Spice” or other smoking mixtures. The synthetic cannabinoids fall into seven major structural groups (Figure 2):

  1. Naphthoylindoles (e.g., JWH-018, JWH-073, JWH-398).
  2. Naphthylmethylindoles. (e.g., JWH-175, JWH-195, JWH-197).
  3. Naphthoylpyrroles.(e.g., JWH-030, JWH-156, JWH-243).
  4. Naphthylmethylindenes (e.g., JWH-176).
  5. Phenylacetylindoles (i.e., benzoylindoles, e.g., JWH-250, JWH-253, JWH-313).
  6. Cyclohexylphenols (e.g., CP 47,497 and homologs of CP 47,497).
  7. Classical cannabinoids (e.g., HU-210).

Compounds in groups 1–5 (JWH compounds) were largely synthesized by Huffman et al. over the past fifteen years (Huffman et al., 1996Wiley et al., 1998Huffman et al., 2000Huffman et al., 2003Huffman et al., 2005Huffman et al., 2006Huffman et al., 2010). The sixth group, cyclohexylphenols, were developed by Pfizer during the 1970’s and 1980’s (Carissimi et al., 1976). The classical cannabinoids (seventh group) is the oldest; synthesis began in the 1960’s following the identification of the chemical structure of THC (Mechoulam and Gaoni, 19651967Gaoni and Mechoulam, 1971). In general, the agonists show little selectivity between CB1 and CB2, while antagonist compounds are highly selective (>1000 fold selective for CB1 vs. CB2 and vice versa with nanomolar affinity at the relevant receptor)(Console-Bram et al., 2012). The selectivity of these antagonists allows the discrimination of CB1- vs. CB2-mediated effects in vitro and in vivo. Despite the existence of numerous non-selective agonists, there are some that exhibit selectivity. For example, HU-308 is a highly selective CB2 agonist with nanomolar affinity at CB2 and >1000 fold selectivity for CB2 vs. CB1. If a compound shows >100 fold selectivity, it is classified as a selective agonist (Console-Bram et al., 2012).

CB signaling – CB-ligand interactions

CB2, as with the rest of the GPCRs, signals through the three main components of the MAPK pathway, namely, ERK, JNK and p38 (Howlett et al., 2002). However, activation of CB receptor coupling to MAPKs is dependent on cellular content. A wide range of activation and inhibition has been observed dependent on cell type, cell differentiation status and co-modulators of MAPK cascades (Howlett, 2005). CB2 agonism decreased CXCR4-activation mediated G-protein activity and MAPK phosphorylation. Furthermore, CB2 agonists altered cytoskeletal reorganization, by decreasing F-actin levels, impairing productive infection (Costantino et al., 2012). Signaling events associated with inflammatory responses in endothelial cells and monocytes are complex; few studies have addressed potential mechanisms of anti-inflammatory CB2 stimulation. Gertsch et al. investigated intracellular signaling pathways triggered in monocytes by LPS-triggered TNFα and IL-1β production that were suppressed by CB2 agonist. LPS treatment of human monocytes led to a rapid phosphorylation of p38 and JNK1/2 (Gertsch et al., 2008), and CB2 agonist reduced Erk1/2 and JNK1/2 activation (phosphorylation)(Gertsch et al., 2008). Whether or not CB2 modulates ion channels has been controversial. Felder and colleagues (Felder et al., 1995) suggested that CB2 does not modulate potassium or high-voltage calcium channels. More recent work indicates that CB2agonists do modulate these channels and earlier results were due to functional selectivity of the ligands used (Atwood et al., 2012). CB2 affects additional signaling pathways, including activation of phospholipase C, leading to release of calcium (Shoemaker et al., 2005), regulation of small G proteins (such as Rho, Rac and cdc42) (Kurihara et al., 2006), and activation of JNK via the phosphatidyl inositol 3 kinase (PI3K)/Akt pathway (Viscomi et al., 2009Atwood et al., 2012). In human umbilical vein endothelial cells, cannabidiol could evoke phosphorylation of p44/42 MAPK and PKB/Akt via PI3K pathway (Offertaler et al., 2003).

GPCRs are regulated at many levels. In general, once they are activated by ligand binding, their signaling is attenuated by a desensitization process, followed by internalization. Desensitization involves G protein receptor kinase-mediated phosphorylation of multiple serine or threonine residues of GPCR, followed by binding of the β-arestins. This protein complex is usually localized to clathrin-coated pits or caveoli where it is internalized. The internalized receptor might be transported to endosomes for dephosphorylation and returned to the plasma membrane for the next signaling event or directed to lysosomes for degradation (Atwood et al., 2012). Little is known about the processes involved in CB2 adaption to chronic activation. Most of the knowledge comes primarily from cell lines over expressing CB2. Although the levels of expression in those systems significantly exceed in vivo CB2 levels, the use of expression systems provides very valuable information (Atwood et al., 2012).

CB2 receptor expression in immune and neuroimmune cells

Anti-inflammatory effects of cannabinoids

The two well-characterized CBs possess different physiological properties. The psychoactive effects of cannabinoids are associated with CB1; CB2 mainly mediates anti-inflammatory and immunomodulatory actions (Miller and Stella, 2008). Identification of CB1 and CB2 resulted in the recognition of endogenous cannabinoids (endocannabinoids) (Pacher et al., 2006). Two endocannabinoid metabolizing enzymes were identified: fatty acid amine hydrolase (FAAH) and monoacylglycerol lipase. CB1 agonists possess neuroprotective properties via diminishing excitotoxicity in postsynaptic neurons (Marsicano et al., 2003), enhancing vasodilation through CB1in vascular smooth muscle and the inhibition of endothelin-1 (Ronco et al., 2007), and decreasing the release of pro-inflammatory mediators including nitric oxide (NO) and tumor necrosis factor (TNFα) in the acute phase of injury (Fernandez-Lopez et al., 2006Panikashvili et al., 2006). Besides their involvement in controlling exitotoxicity and inflammation, compelling evidence shows that CB1receptors in the CNS play an important role in neuroprotection (Sanchez and Garcia-Merino, 2011). CB1-deficient mice were more susceptible for experimental autoimmune encephalomyelitis (EAE), had more neurodegeneration and had worse recovery, compared to wild type mice (Maresz et al., 2007). The presence of CB1 in neurons, but not in T-cells, was an essential requisite for cannabinoid-mediated neuroprotection in EAE. The therapeutic limitations of CB1 agonists are related to the very short window of their beneficial actions and psychoactive effects at effective doses. CB2 agonists are devoid of psychoactive activities. Because neuroinflammation plays a significant role in essentially all neurodegenerative processes, CB2 stimulation became an attractive target for development of neuroprotective therapies. CB2 is expressed in different types of leukocytes mediating cannabinoid anti-inflammatory effects and immunomodulation (McKallip et al., 2002bMcKallip et al., 2002a).

Cannabinoid induced immunomodulation

The mechanism of cannabinoid-induced immunomodulation has been studied in both in vitro and in vivo systems; however, still many questions remain unanswered. It is known that cannabinoids bind to CB1 and CB2 inhibiting adenylate cyclase activity and preventing forskolin-stimulated cAMP activation. This process leads to decreased activity of protein kinase A and subsequently lesser binding of transcription factors to CRE consensus sequences (Condie et al., 1996Rieder et al., 2010). Cannabinoids clearly modulate immune responses during inflammatory processes and their immunomodulatory effects have been studied in many disease models such as MS, diabetes, septic shock, rheumatoid arthritis, and others (Table 1 and Table 2). Results of animal studies show that cannabinoids exert their immunomodulatory properties in four ways: i) induction of apoptosis, ii) suppression of cell proliferation, iii) inhibition of pro-inflammatory cytokine/chemokine production and increase in anti-inflammatory cytokines, and iv) induction of regulatory T cells (Rieder et al., 2010). It has been shown that THC inhibits proliferation of human lymphocytes in culture (Schwarz et al., 1994) and leads to apoptosis of murine macrophages and T cells (Zhu et al., 1998). McKallip and colleagues showed that THC affects naïve lymphocytes to a greater degree than activated lymphocyte (McKallip et al., 2002b). It was also noted that activated lymphocytes had less expression of CB2, thereby explaining the decreased sensitivity of activated lymphocytes to THC (McKallip et al., 2002b). JWH-015, a CB2 synthetic agonist, inhibited proliferation in T and B cells in a dose-dependent manner and induced apoptosis in splenocytes and thymocytes (Lombard et al., 2007Rieder et al., 2010). Derocq and colleagues (Derocq et al., 1995) demonstrated that the activity of cannabinoids is not restricted to immunomodulation, and in nanomolar concentrations of synthetic (CP55,940 and WIN55212-2) and natural (THC) cannabinoids increase proliferation of B cells co-stimulated with anti-CD40-antibodies, while at micromolar range (1–100 M) the same cannabinoids inhibited proliferation (Derocq et al., 1995). Interestingly, cannabinol and THC protected human B lymphoblastoid cell line from serum-deprived cell-death and oxidative stress in sub-micromolar concentrations (Chen and Buck, 2000). The fact that activation of CB2 triggers apoptosis in immune cells suggests that targeting CB2 may be a novel approach to the treatment of inflammatory and autoimmune diseases.

Table 1

Anti-inflammatory effects of CB2 activation on immune and neuroimmune cells
Table 2

Anti-inflammatory effects of CB2 activation in animal models

CB2 expression in CNS and its mediated anti-neuroinflammatory responses

CB2 expression has been detected in microglia. Carlisle et al. (Carlisle et al., 2002) found CB1 and CB2 mRNA in brain tissue and in primary rat microglia cultures. CB2 expression in microglia is up-regulated during activation. Neuroprotective effects of CB2 agonists are associated with suppression of microglia activation (Klegeris et al., 2003Eljaschewitsch et al., 2006) via inhibiting the release of neurotoxic factors and by decreasing neuronal cell damage in cell or tissue culture models.

Increased expression of CB2 under neuroinflammatory conditions was found in human brain (Benito et al., 2008). Prominent CB2 upregulation was reported in brain tissues affected by MS, amyotrophic lateral sclerosis (ALS), Down syndrome and Alzheimer’s disease, AD (Benito et al., 2005Yiangou et al., 2006Benito et al., 2007Benito et al., 2008Solas et al., 2012). Enhanced CB2 expression was detected on microglia, perivascular macrophages and T cells in simian immunodeficiency virus encephalitis, model of HIV-1 infection that paralleled FAAH over-expression in astrocytes (Benito et al., 2005). Increased expression of CB2 on microglia/perivascular macrophages and brain microvascular endothelial cells were found in HIV-1 encephalitis, brain endothelium in HIV+ cases (without encephalitis) and very little in non-infected control human brains (Persidsky et al., 2011). CB2 agonist prevented neuronal injury during neuroinflammation via upregulation of mitogen-activated protein kinase phosphatase-1 that resulted in Erk1/2 inhibition (Eljaschewitsch et al., 2006). CB2 stimulation specifically reduced iNOS production via inhibition of ERK-1/2 phosphorylation in microglia during CNS inflammation (Merighi et al., 2011). These findings have relevance to anti-inflammatory effects of CB2 stimulation in brain. CB2-mediated regulation of this pathway could be very important for cannabinoid regulation of neuroinflammation. Anti-inflammatory and neuroprotective effects of cannabinoids have been confirmed in animal models for MS, AD, stroke, ALS, and other animal models of diverse inflammatory diseases (summarized in Table 2). In summary, cannabinoids can be neuroprotective via their immunomodulatory properties, which have been mainly attributed to CB2 receptors.

CB receptors in leukocytes and endothelium: relevance to HIV infection

Cannabinoids can affect different pro-inflammatory events associated with HIV infection, such as: i) chemotaxis of immune cells, ii) activation of endothelium and leukocyte infiltration into tissues, iii) injury of endothelial barriers, like the blood brain barrier (BBB), and iv) HIV-1 infection of susceptible cells.

CB2 appears to play a major role in leukocyte migration. Human monocytes treated with the synthetic CB2 agonist, JWH-015, showed diminished migration in response to the chemokines, CCL2 and CCL3, via down-regulation of their receptors and inhibition of IFNγ-induced ICAM-1 expression. Leukocyte migration mediated by RhoA activation was inhibited by CB2 agonists (Kurihara et al., 2006). Cannabinoids could reduce inflammation by interfering with the action of other chemoattractants (Montecucco et al., 2008). Cannabinoids have been reported to inhibit chemokine-induced chemotaxis of various cell types including neutrophils, lymphocytes, macrophages, monocytes and microglia (Miller and Stella, 2008). Recently, it has been shown that CB2 agonist affected dendritic cell migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase-9 expression (Adhikary et al., 2012).

In addition to putative effects on leukocytes, anti-inflammatory properties of CB agonists may be related to their actions on the endothelium. CB2 has been found in brain endothelium (Golech et al., 2004Lu et al., 2008) and in endothelial cells from other organs (Rajesh et al., 2007). Synthetic CB2agonists (JWH-133, HU-308) reduced TNFα-induced activation of human coronary artery endothelial cells in vitro. CB2 agonists reduced secretion of MCP-1 and attenuated monocyte transendothelial migration (Rajesh et al., 2007). Those results are relevant to CB2 anti-inflammatory effects.

Lu and colleagues (Lu et al., 2008) demonstrated that HIV-1 gp120 caused secretion of substance P and dysfunction of brain endothelial cells (Ca2+ influx, decreased barrier tightness, decrease in tight junction (TJ) expression) that was prevented by non-selective CB1/CB2 or CB1 agonists. These compounds diminished monocyte migration across endothelial monolayers pretreated with gp120. The molecular mechanism underlying the beneficial effects of CB agonists was not investigated. Because CB2 agonists modulate immune cell migration, they represent a promising pharmacological approach for development of anti-inflammatory therapeutics. Fraga and colleagues (Fraga et al., 2011) found that CB2 inhibited migration of microglial cells toward HIV Tat protein in a mouse BV-2 microglia-like cell model. In addition, the level of the β-chemokine receptor CCR3 was reduced and its localization was altered.

Our group investigated the effects of CB2 receptor agonists (JWH133 and O1966) on leukocyte-brain endothelial cell interactions. Using primary human brain microvascular endothelial cells and human monocytes, we showed diminished adhesion of leukocytes to activated endothelium and down-regulation of adhesion molecules. In an animal model of systemic inflammation, leukocyte adhesion was significantly attenuated in postcapillary venules in animals treated with CB2 agonists. BBB injury and increased permeability were prevented (Ramirez et al., 2012).

The CB2 agonist, JWH133, was shown to inhibit HIV-1 infection in primary CD4+ T lymphocytes by altering T cell actin dynamics via inactivation of the actin-modulating protein, cofilin. Actin rearrangements are essential for productive infection. CB2 agonist did not alter CXCR4 expression, T cell activation or viral fusion (Costantino et al., 2012). We showed that CB2 agonists diminished HIV replication and HIV LTR activation in monocyte-derived macrophages (personal communication). Cannabimimetic drugs are of particular relevance to HIV-1 associated neurocognitive disorders (HAND) because of their clinical and illicit use in patients with AIDS. The cannabinoid receptor agonist, Win55,212–2, inhibited HIV-1 gp120-induced IL-1β production and synapse loss in a manner reversed by CB2 receptor antagonist. In contrast, Win55,212–2 did not inhibit synapse loss elicited by exposure to the HIV-1 protein Tat. These results indicate that cannabinoids prevent the impairment of network function produced by gp120 and, thus, might have therapeutic potential in HAND (Kim et al., 2011). Molina and colleagues (Molina et al., 2010Molina et al., 2011) demonstrated that that chronic Δ9-THC treatment decreased plasma and cerebrospinal fluid (CSF) viral load and tissue inflammation significantly reducing morbidity and mortality of simian immunodeficiency virus-infected macaques. THC treatment led to better maintenance of body weight without any alterations in immune responses (Molina et al., 2010). Win55,212–2 has been shown to inhibit HIV-1 expression in CD4+ lymphocytes and microglial cell cultures in a time- and dose-dependant manner (Peterson et al., 2004). Taken together, these studies point to potential therapeutic benefits of CB stimulation in treatment of HIV-1 infection.


The full potential of CB2 agonists as therapeutic agents remains to be realized. Despite some inadequacies of preclinical models to predict clinical efficacy in humans and differences between the signaling of human and rodent CB2 receptors, the development of selective CB2 agonists may open new avenues in therapeutic intervention. Such interventions would aim at reducing the release of pro-inflammatory mediators particularly in chronic neuropathologic conditions such as HAND or MS. Further studies are needed to delineate the therapeutic effects of CB2 agonists in current efforts to legalize the use of marijuana for medical purposes.


This work was supported in part by NIH Grants AA017398, MH065151, DA025566, and AA015913 (Y.P.). The authors express their grateful acknowledgement for proofreading and editing to Nancy L. Reichenbach.


  • Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515–521.  [PubMed]
  • Adhikary S, Kocieda VP, Yen JH, Tuma RF, Ganea D. Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression. Blood. 2012;120:3741–3749. [PMC free article]  [PubMed]
  • Ahn KH, Pellegrini M, Tsomaia N, Yatawara AK, Kendall DA, Mierke DF. Structural analysis of the human cannabinoid receptor one carboxyl-terminus identifies two amphipathic helices. Biopolymers. 2009;91:565–573. [PMC free article]  [PubMed]
  • Anday JK, Mercier RW. Gene ancestry of the cannabinoid receptor family. Pharmacological Research. 2005;52:463–466.  [PubMed]
  • Ashton CH, Moore PB. Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand. 2011;124:250–261.  [PubMed]
  • Ashton JC, Rahman RM, Nair SM, Sutherland BA, Glass M, Appleton I. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett. 2007;412:114–117.  [PubMed]
  • Atwood BK, Straiker A, Mackie K. CB(2): therapeutic target-in-waiting. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:16–20. [PMC free article]  [PubMed]
  • Azorlosa JL, Heishman SJ, Stitzer ML, Mahaffey JM. Marijuana smoking: effect of varying delta 9-tetrahydrocannabinol content and number of puffs. J Pharmacol Exp Ther. 1992;261:114–122.  [PubMed]
  • Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di Marzo V. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 2001;15:300–302.  [PubMed]
  • Barbato L.  Dronabinol treatment for migraine. US: 2007. 
  • Bari M, Spagnuolo P, Fezza F, Oddi S, Pasquariello N, Finazzi-Agro A, Maccarrone M. Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells. J Immunol. 2006;177:4971–4980.  [PubMed]
  • Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006;105:1–25.  [PubMed]
  • Benito C, Tolon RM, Pazos MR, Nunez E, Castillo AI, Romero J. Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol. 2008;153:277–285.[PMC free article]  [PubMed]
  • Benito C, Kim WK, Chavarria I, Hillard CJ, Mackie K, Tolon RM, Williams K, Romero J. A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis. J Neurosci. 2005;25:2530–2536.  [PubMed]
  • Benito C, Romero JP, Tolon RM, Clemente D, Docagne F, Hillard CJ, Guaza C, Romero J. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007;27:2396–2402.  [PubMed]
  • Berdyshev E, Boichot E, Corbel M, Germain N, Lagente V. Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice. Life Sci. 1998;63:PL125–129.[PubMed]
  • Carissimi M, Gentili P, Grumelli E, Milla E, Picciola G, Ravenna F. Basic ethers of cyclohexylphenols with beta-blocking activity: synthesis and pharmacological study of exaprolol. Arzneimittelforschung. 1976;26:506–516.  [PubMed]
  • Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA. Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol. 2002;2:69–82.  [PubMed]
  • Chen Y, Buck J. Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther. 2000;293:807–812.  [PubMed]
  • Chuchawankul S, Shima M, Buckley NE, Hartmann CB, McCoy KL. Role of cannabinoid receptors in inhibiting macrophage costimulatory activity. Int Immunopharmacol. 2004;4:265–278.  [PubMed]
  • Condie R, Herring A, Koh WS, Lee M, Kaminski NE. Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2. J Biol Chem. 1996;271:13175–13183.  [PubMed]
  • Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012[PMC free article]  [PubMed]
  • Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G. Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol. 2002;135:181–187. [PMC free article][PubMed]
  • Correa F, Docagne F, Mestre L, Clemente D, Hernangomez M, Loria F, Guaza C. A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells. Biochem Pharmacol. 2009;77:86–100.  [PubMed]
  • Costantino CM, Gupta A, Yewdall AW, Dale BM, Devi LA, Chen BK. Cannabinoid receptor 2-mediated attenuation of CXCR4-tropic HIV infection in primary CD4+ T cells. PLoS One. 2012;7:e33961. [PMC free article]  [PubMed]
  • Crandall J, Matragoon S, Khalifa YM, Borlongan C, Tsai NT, Caldwell RB, Liou GI. Neuroprotective and intraocular pressure-lowering effects of (-)Delta9-tetrahydrocannabinol in a rat model of glaucoma. Ophthalmic Res. 2007;39:69–75.  [PubMed]
  • Crippa JA, Zuardi AW. Duloxetine in the treatment of panic disorder. Int J Neuropsychopharmacol. 2006;9:633–634.  [PubMed]
  • Dainese E, Oddi S, Maccarrone M. Lipid-mediated dimerization of beta2-adrenergic receptor reveals important clues for cannabinoid receptors. Cell Mol Life Sci. 2008;65:2277–2279.[PubMed]
  • Dejesus E, Rodwick BM, Bowers D, Cohen CJ, Pearce D. Use of Dronabinol Improves Appetite and Reverses Weight Loss in HIV/AIDS-Infected Patients. J Int Assoc Physicians AIDS Care (Chic) 2007;6:95–100.  [PubMed]
  • Derocq JM, Segui M, Marchand J, Le Fur G, Casellas P. Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett. 1995;369:177–182.  [PubMed]
  • Devane WA, Dysarz FA, 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–613.[PubMed]
  • Docagne F, Muneton V, Clemente D, Ali C, Loria F, Correa F, Hernangomez M, Mestre L, Vivien D, Guaza C. Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation. Mol Cell Neurosci. 2007;34:551–561.  [PubMed]
  • El-Remessy AB, Tang Y, Zhu G, Matragoon S, Khalifa Y, Liu EK, Liu JY, Hanson E, Mian S, Fatteh N, Liou GI. Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation. Mol Vis. 2008;14:2190–2203. [PMC free article][PubMed]
  • Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron. 2006;49:67–79.  [PubMed]
  • Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26:485–495.  [PubMed]
  • Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A. Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia. 2003;41:161–168.  [PubMed]
  • Fan P. Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J Neurophysiol. 1995;73:907–910.  [PubMed]
  • Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995;48:443–450.  [PubMed]
  • Fernandez-Lopez D, Martinez-Orgado J, Nunez E, Romero J, Lorenzo P, Moro MA, Lizasoain I. Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res. 2006;60:169–173.  [PubMed]
  • Fraga D, Raborn ES, Ferreira GA, Cabral GA. Cannabinoids inhibit migration of microglial-like cells to the HIV protein Tat. J Neuroimmune Pharmacol. 2011;6:566–577.  [PubMed]
  • Gaoni Y, Mechoulam R. The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc. 1971;93:217–224.  [PubMed]
  • Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. 2008;105:9099–9104. [PMC free article]  [PubMed]
  • Golech SA, McCarron RM, Chen Y, Bembry J, Lenz F, Mechoulam R, Shohami E, Spatz M. Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res Mol Brain Res. 2004;132:87–92.  [PubMed]
  • Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95:8268–8273. [PMC free article]  [PubMed]
  • Han KH, Lim S, Ryu J, Lee CW, Kim Y, Kang JH, Kang SS, Ahn YK, Park CS, Kim JJ. CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc Res. 2009;84:378–386.  [PubMed]
  • Heishman SJ, Stitzer ML, Yingling JE. Effects of tetrahydrocannabinol content on marijuana smoking behavior, subjective reports, and performance. Pharmacol Biochem Behav. 1989;34:173–179.  [PubMed]
  • Howlett AC. Cannabinoid receptor signaling. Handb Exp Pharmacol. 2005:53–79.  [PubMed]
  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202.  [PubMed]
  • Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:1770–1804.[PMC free article]  [PubMed]
  • Huffman JW, Padgett LW, Isherwood ML, Wiley JL, Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: new high affinity ligands for the cannabinoid CB1 and CB2 receptors. Bioorg Med Chem Lett. 2006;16:5432–5435.  [PubMed]
  • Huffman JW, Lu J, Dai D, Kitaygorodskiy A, Wiley JL, Martin BR. Synthesis and pharmacology of a hybrid cannabinoid. Bioorg Med Chem. 2000;8:439–447.  [PubMed]
  • Huffman JW, Hepburn SA, Lyutenko N, Thompson AL, Wiley JL, Selley DE, Martin BR. 1-Bromo-3-(1′,1′-dimethylalkyl)-1-deoxy-Delta(8)-tetrahydrocannabinols: New selective ligands for the cannabinoid CB(2) receptor. Bioorg Med Chem. 2010;18:7809–7815.[PMC free article]  [PubMed]
  • Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH. Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J Med Chem. 1996;39:3875–3877.[PubMed]
  • Huffman JW, Mabon R, Wu MJ, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR. 3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor. Bioorg Med Chem. 2003;11:539–549.  [PubMed]
  • Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, Bushell K, Thompson AL, Bushell S, Tartal C, Hurst DP, Reggio PH, Selley DE, Cassidy MP, Wiley JL, Martin BR. Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg Med Chem. 2005;13:89–112.  [PubMed]
  • Karst M, Wippermann S, Ahrens J. Role of cannabinoids in the treatment of pain and (painful) spasticity. Drugs. 2010;70:2409–2438.  [PubMed]
  • Kim HJ, Shin AH, Thayer SA. Activation of cannabinoid type 2 receptors inhibits HIV-1 envelope glycoprotein gp120-induced synapse loss. Mol Pharmacol. 2011;80:357–366.[PMC free article]  [PubMed]
  • Kim K, Moore DH, Makriyannis A, Abood ME. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur J Pharmacol. 2006;542:100–105.  [PubMed]
  • Klegeris A, Bissonnette CJ, McGeer PL. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol. 2003;139:775–786. [PMC free article]  [PubMed]
  • Kogan NM, Schlesinger M, Peters M, Marincheva G, Beeri R, Mechoulam R. A cannabinoid anticancer quinone, HU-331, is more potent and less cardiotoxic than doxorubicin: a comparative in vivo study. J Pharmacol Exp Ther. 2007;322:646–653.  [PubMed]
  • Krymchantowski AV, da Jevoux CC. The experience of combining agents, specially triptans and non steroidal anti-inflammatory drugs, for the acute treatment of migraine – a review. Recent Pat CNS Drug Discov. 2007;2:141–144.  [PubMed]
  • Kurihara R, Tohyama Y, Matsusaka S, Naruse H, Kinoshita E, Tsujioka T, Katsumata Y, Yamamura H. Effects of peripheral cannabinoid receptor ligands on motility and polarization in neutrophil-like HL60 cells and human neutrophils. J Biol Chem. 2006;281:12908–12918.[PubMed]
  • Lakhan SE, Rowland M. Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC Neurol. 2009;9:59. [PMC free article]  [PubMed]
  • Law B, Mason PA, Moffat AC, Gleadle RI, King LJ. Forensic aspects of the metabolism and excretion of cannabinoids following oral ingestion of cannabis resin. J Pharm Pharmacol. 1984;36:289–294.  [PubMed]
  • Lee SF, Newton C, Widen R, Friedman H, Klein TW. Differential expression of cannabinoid CB(2) receptor mRNA in mouse immune cell subpopulations and following B cell stimulation. Eur J Pharmacol. 2001;423:235–241.  [PubMed]
  • Leussink VI, Husseini L, Warnke C, Broussalis E, Hartung HP, Kieseier BC. Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity. Ther Adv Neurol Disord. 2012;5:255–266. [PMC free article]  [PubMed]
  • Liu QR, Pan CH, Hishimoto A, Li CY, Xi ZX, Llorente-Berzal A, Viveros MP, Ishiguro H, Arinami T, Onaivi ES, Uhl GR. Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav. 2009;8:519–530.[PMC free article]  [PubMed]
  • Lombard C, Nagarkatti M, Nagarkatti P. CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents. Clin Immunol. 2007;122:259–270. [PMC free article]  [PubMed]
  • Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, Pecker F, Mallat A, Lotersztajn S. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011;54:1217–1226.  [PubMed]
  • Lu TS, Avraham HK, Seng S, Tachado SD, Koziel H, Makriyannis A, Avraham S. Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells. J Immunol. 2008;181:6406–6416. [PMC free article]  [PubMed]
  • Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK. Novel cannabinol probes for CB1 and CB2 cannabinoid receptors. J Med Chem. 2000;43:3778–3785.  [PubMed]
  • Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, Giovannoni G, Pertwee RG, Yamamura T, Buckley NE, Hillard CJ, Lutz B, Baker D, Dittel BN. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med. 2007;13:492–497.  [PubMed]
  • Marsicano G, Lutz B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci. 1999;11:4213–4225.  [PubMed]
  • Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302:84–88.  [PubMed]
  • Martin-Moreno AM, Brera B, Spuch C, Carro E, Garcia-Garcia L, Delgado M, Pozo MA, Innamorato NG, Cuadrado A, Ceballos ML. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflammation. 2012;9:8. [PMC free article]  [PubMed]
  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561–564.[PubMed]
  • Maurer M, Henn V, Dittrich A, Hofmann A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Clin Neurosci. 1990;240:1–4.  [PubMed]
  • McKallip RJ, Lombard C, Martin BR, Nagarkatti M, Nagarkatti PS. Delta(9)-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo. J Pharmacol Exp Ther. 2002a;302:451–465.[PubMed]
  • McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti PS, Nagarkatti M. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood. 2002b;100:627–634.  [PubMed]
  • Mechoulam R, Gaoni Y, Hashish IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron. 1965;21:1223–1229.  [PubMed]
  • Mechoulam R, Gaoni Y. Recent advances in the chemistry of hashish. Fortschr Chem Org Naturst. 1967;25:175–213.  [PubMed]
  • Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol–recent advances. Chem Biodivers. 2007;4:1678–1692.  [PubMed]
  • Merighi S, Gessi S, Varani K, Simioni C, Fazzi D, Mirandola P, Borea PA. Cannabinoid CB(2) receptors modulate ERK-1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide. Br J Pharmacol. 2011;165:1773–1788.[PMC free article]  [PubMed]
  • Mestre L, Docagne F, Correa F, Loria F, Hernangomez M, Borrell J, Guaza C. A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules. Mol Cell Neurosci. 2009;40:258–266.  [PubMed]
  • Miller AM, Stella N. CB2 receptor-mediated migration of immune cells: it can go either way. Br J Pharmacol. 2008;153:299–308. [PMC free article]  [PubMed]
  • Molina PE, Amedee A, LeCapitaine NJ, Zabaleta J, Mohan M, Winsauer P, Vande Stouwe C. Cannabinoid neuroimmune modulation of SIV disease. J Neuroimmune Pharmacol. 2011;6:516–527. [PMC free article]  [PubMed]
  • Molina PE, Winsauer P, Zhang P, Walker E, Birke L, Amedee A, Stouwe CV, Troxclair D, McGoey R, Varner K, Byerley L, Lamotte L. Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus. AIDS Res Hum Retroviruses 2010[PMC free article]  [PubMed]
  • Molina-Holgado F, Molina-Holgado E, Guaza C. The endogenous cannabinoid anandamide potentiates interleukin-6 production by astrocytes infected with Theiler’s murine encephalomyelitis virus by a receptor-mediated pathway. FEBS Lett. 1998;433:139–142.[PubMed]
  • Montecucco F, Burger F, Mach F, Steffens S. CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol. 2008;294:H1145–1155.  [PubMed]
  • Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–65.  [PubMed]
  • Murikinati S, Juttler E, Keinert T, Ridder DA, Muhammad S, Waibler Z, Ledent C, Zimmer A, Kalinke U, Schwaninger M. Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. FASEB J. 2010;24:788–798.[PubMed]
  • Nunez E, Benito C, Pazos MR, Barbachano A, Fajardo O, Gonzalez S, Tolon RM, Romero J. Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004;53:208–213.  [PubMed]
  • Offertaler L, Mo FM, Batkai S, Liu J, Begg M, Razdan RK, Martin BR, Bukoski RD, Kunos G. Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol. 2003;63:699–705.  [PubMed]
  • Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462. [PMC free article]  [PubMed]
  • Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science. 2000;289:739–745.  [PubMed]
  • Panikashvili D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A, Shohami E. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Dis. 2006;22:257–264.  [PubMed]
  • Persidsky Y, Ho W, Ramirez SH, Potula R, Abood ME, Unterwald E, Tuma R. HIV-1 infection and alcohol abuse: neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions. Brain Behav Immun. 2011;25(Suppl 1):S61–70.[PMC free article]  [PubMed]
  • Peterson PK, Gekker G, Hu S, Cabral G, Lokensgard JR. Cannabinoids and morphine differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures. J Neuroimmunol. 2004;147:123–126.  [PubMed]
  • Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295:761–775.  [PubMed]
  • Pini A, Mannaioni G, Pellegrini-Giampietro D, Passani MB, Mastroianni R, Bani D, Masini E. The role of cannabinoids in inflammatory modulation of allergic respiratory disorders, inflammatory pain and ischemic stroke. Curr Drug Targets. 2012;13:984–993.  [PubMed]
  • Pryce G, Baker D. Emerging properties of cannabinoid medicines in management of multiple sclerosis. Trends Neurosci. 2005;28:272–276.  [PubMed]
  • Puffenbarger RA, Boothe AC, Cabral GA. Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia. 2000;29:58–69.  [PubMed]
  • Racz I, Nadal X, Alferink J, Banos JE, Rehnelt J, Martin M, Pintado B, Gutierrez-Adan A, Sanguino E, Bellora N, Manzanares J, Zimmer A, Maldonado R. Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci. 2008;28:12136–12145. [PMC free article]  [PubMed]
  • Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P. CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol. 2007;293:H2210–2218.[PMC free article]  [PubMed]
  • Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25:1904–1913.  [PubMed]
  • Ramirez SH, Hasko J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y. Activation of Cannabinoid Receptor 2 Attenuates Leukocyte-Endothelial Cell Interactions and Blood-Brain Barrier Dysfunction under Inflammatory Conditions. J Neurosci. 2012;32:4004–4016. [PMC free article][PubMed]
  • Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology. 2010;215:598–605.[PMC free article]  [PubMed]
  • Ronco AM, Llanos M, Tamayo D, Hirsch S. Anandamide inhibits endothelin-1 production by human cultured endothelial cells: a new vascular action of this endocannabinoid. Pharmacology. 2007;79:12–16.  [PubMed]
  • Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers. 2007;4:1729–1743.  [PubMed]
  • Ryberg E, Vu HK, Larsson N, Groblewski T, Hjorth S, Elebring T, Sjogren S, Greasley PJ. Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett. 2005;579:259–264.  [PubMed]
  • Sanchez AJ, Garcia-Merino A. Neuroprotective agents: cannabinoids. Clin Immunol. 2011;142:57–67.  [PubMed]
  • Sarfaraz S, Adhami VM, Syed DN, Afaq F, Mukhtar H. Cannabinoids for cancer treatment: progress and promise. Cancer Res. 2008;68:339–342.  [PubMed]
  • Sastre-Garriga J, Vila C, Clissold S, Montalban X. THC and CBD oromucosal spray (Sativex(R)) in the management of spasticity associated with multiple sclerosis. Expert Rev Neurother. 2007;11:627–637.  [PubMed]
  • Schwarz H, Blanco FJ, Lotz M. Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J Neuroimmunol. 1994;55:107–115.[PubMed]
  • Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL. Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors. J Pharmacol Exp Ther. 2005;315:828–838.[PubMed]
  • Solas M, Francis PT, Franco R, Ramirez MJ. CB(2) receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol Aging 2012  [PubMed]
  • Storr MA, Keenan CM, Zhang H, Patel KD, Makriyannis A, Sharkey KA. Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis. Inflamm Bowel Dis. 2009;15:1678–1685.  [PubMed]
  • Tao Q, McAllister SD, Andreassi J, Nowell KW, Cabral GA, Hurst DP, Bachtel K, Ekman MC, Reggio PH, Abood ME. Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Mol Pharmacol. 1999;55:605–613.  [PubMed]
  • Todaro B. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw. 2012;10:487–492.  [PubMed]
  • Tschop J, Kasten KR, Nogueiras R, Goetzman HS, Cave CM, England LG, Dattilo J, Lentsch AB, Tschop MH, Caldwell CC. The cannabinoid receptor 2 is critical for the host response to sepsis. J Immunol. 2009;183:499–505. [PMC free article]  [PubMed]
  • Tuma RF, Steffens S. Targeting the endocannabinod system to limit myocardial and cerebral ischemic and reperfusion injury. Curr Pharm Biotechnol. 2012;13:46–58.  [PubMed]
  • Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos GG. The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol. 2003;138:544–553. [PMC free article]  [PubMed]
  • Viscomi MT, Oddi S, Latini L, Pasquariello N, Florenzano F, Bernardi G, Molinari M, Maccarrone M. Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci. 2009;29:4564–4570.[PubMed]
  • Wiley JL, Compton DR, Dai D, Lainton JA, Phillips M, Huffman JW, Martin BR. Structure-activity relationships of indole- and pyrrole-derived cannabinoids. J Pharmacol Exp Ther. 1998;285:995–1004.  [PubMed]
  • Williams PB, Martin BR, Lattanzio FA, Samudre S, Razdan RK.  NOVEL CANNABINOIDS AND METHODS OF USE. 2007. 
  • Witkin JM, Tzavara ET, Davis RJ, Li X, Nomikos GG. A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders. Trends Pharmacol Sci. 2005;26:609–617.  [PubMed]
  • Woelkart K, Salo-Ahen OM, Bauer R. CB receptor ligands from plants. Curr Top Med Chem. 2008;8:173–186.  [PubMed]
  • Xiao JC, Jewell JP, Lin LS, Hagmann WK, Fong TM, Shen CP. Similar in vitro pharmacology of human cannabinoid CB1 receptor variants expressed in CHO cells. Brain Res. 2008;1238:36–43.  [PubMed]
  • Xie XQ, Chen JZ. NMR structural comparison of the cytoplasmic juxtamembrane domains of G-protein-coupled CB1 and CB2 receptors in membrane mimetic dodecylphosphocholine micelles. J Biol Chem. 2005;280:3605–3612.  [PubMed]
  • Xie XQ, Chen JZ, Billings EM. 3D structural model of the G-protein-coupled cannabinoid CB2 receptor. Proteins. 2003;53:307–319.  [PubMed]
  • Yao B, Mackie K. Endocannabinoid receptor pharmacology. Curr Top Behav Neurosci. 2009;1:37–63.  [PubMed]
  • Yazulla S. Endocannabinoids in the retina: from marijuana to neuroprotection. Prog Retin Eye Res. 2008;27:501–526. [PMC free article]  [PubMed]
  • Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006;6:12. [PMC free article]  [PubMed]
  • Yu XH, Cao CQ, Martino G, Puma C, Morinville A, St-Onge S, Lessard E, Perkins MN, Laird JM. A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain. 2010;151:337–344.  [PubMed]
  • Zhang M, Martin BR, Adler MW, Razdan RK, Jallo JI, Tuma RF. Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia/reperfusion model. J Cereb Blood Flow Metab. 2007;27:1387–1396. [PMC free article]  [PubMed]
  • Zhang M, Adler MW, Abood ME, Ganea D, Jallo J, Tuma RF. CB2 receptor activation attenuates microcirculatory dysfunction during cerebral ischemic/reperfusion injury. Microvasc Res. 2009;78:86–94. [PMC free article]  [PubMed]
  • Zhu W, Friedman H, Klein TW. Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. J Pharmacol Exp Ther. 1998;286:1103–1109.  [PubMed]
  • Ziring D, Wei B, Velazquez P, Schrage M, Buckley NE, Braun J. Formation of B and T cell subsets require the cannabinoid receptor CB2. Immunogenetics. 2006;58:714–725.  [PubMed]
  • Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006a;39:421–429.[PubMed]
  • Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF, Musty RE, Crippa JA. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006b;20:683–686.  [PubMed]