The endocannabinoid signaling system is a widespread, neuromodulatory system in brain and is also widely utilized in the periphery to modulate metabolic functions and the immune system. Preclinical data demonstrate that endocannabinoid signaling is an important stress buffer and modulates emotional and cognitive functions. These data suggest the hypothesis that endocannabinoid signaling could be dysfunctional in a number of mental disorders. Genetic polymorphisms in the human genes for two important proteins of the endocannabinoid signaling system, the CB1 cannabinoid receptor (CB1R) and fatty acid amide hydrolase (FAAH), have been explored in the context of normal and pathological conditions. In the case the gene for FAAH, the mechanistic relationships among the common genetic polymorphism, the expression of the FAAH protein and its likely impact on endocannabinoid signaling are understood. However, multiple polymorphisms in the gene for the CB1R occur and are associated with human phenotypic differences without an understanding of the functional relationships among the gene, mRNA, protein and protein function. The endocannabinoid ligands are found in the circulation and several studies have identified changes in their concentrations under various conditions. These data are reviewed for the purpose of generating hypotheses and to encourage further studies in this very interesting and important area.

2.1 CB1 cannabinoid receptor

 

2.1.4. CNR1 Single Nucleotide Polymorphisms (SNPs)

A frequent mutation in the coding region of exon 4 that is 1359 bp from the translational start site was first reported in 1999 (rs1049353) (Gadzicki et al., 1999); the common nucleotide is G and the rare is A. This is a silent mutation that does not alter the amino acid (threonine) at position 453 in the CB1R protein. Many other SNPs have been identified in and near the CNR1 gene (Herman et al., 2006, Zuo et al., 2007,Baye et al., 2008, Chen et al., 2008, Hamdani et al., 2008, Juhasz et al., 2009b,Ho et al., 2011). Several generalities can be made regarding these heterogeneities. First, none of the identified SNPs result in deletion or mutation of the CB1R protein. Second, several investigators have studied the linkage disequilibrium (LD) among various SNPs in the CNR1 gene and have identified several groups of SNPs that are in LD, meaning that they are inherited together more often than would be predicted if they were independent genes. These groups of SNPs are called “haplotype blocks”, several of the CNR1 haplotype blocks identified are shown in Table 1. Third, as is discussed more fully in part 3 of this review, the data regarding the association of SNPs and haplotypes with mental disorders can be contradictory but there are hints that diversity in the CNR1 gene could contribute in important ways to personality characteristics or other forms of vulnerability to disease.

Table 1

Haplotype blocks of SNPs in CNR1

A very important component to further understanding of the reported associations between CNR1 genotype and any phenotype is knowledge of the consequence of the associated SNP to CB1R function. The discovery of a significant association between a SNP within or in the neighborhood of a gene and a phenotype suggests that a genetic difference contributes to the phenotype being studied. However, it is often the case that the mechanistic basis for the relationship is not obvious. In particular, while the data discussed below demonstrate some very intriguing association between CNR1 SNPs or haplotypes, the mechanistic links are largely unknown. For example, two SNPs in the coding region of exon 4 (rs1049353 (Gadzicki et al., 1999) and rs3505747 (Ho et al., 2011)) of CNR1 occur, one of which (rs1049353) has been significantly associated with several human phenotypes (described in section 4.0). However, neither of these changes in nucleotide results in a changed amino acid, leading to the conclusion that the CB1R protein is identical in humans with the two genotypes. It is possible that the SNPs themselves are not causative at all, but are in LD with a causative SNP or other genetic change. Alternatively, the impact of the SNP on mRNA species could be significant and contribute to the mechanism

There are data available supporting the idea that SNPs can have functional effects on CNR1 through changes in the expression of its mRNA as a result of elimination or creation of a transcription factor binding site. For example, the A allele of rs2180619, a SNP in the 5′ promoter region of CNR1, forms sequences that are more than 90% similar to known binding sites for the glucocorticoid receptor and transcription factor II D (Lazary et al., 2009). Conversely, the presence of a G at this position results in putative binding sites for four different transcription factors: sex-determining region Y gene product, T-cell factor 4E, lymphoid enhancer binding factor 1, and transcription factor 4.

Another SNP in a region of exon 4 that has been proposed to serve as an alternative putative promoter region, rs12720071, is within a potential transcription factor binding site (Heinemeyer et al., 1998). Ho, Andreasen and colleagues (Ho et al., 2011) have pointed out that the common nucleotide at this position (A), but not the rare nucleotide (G), results in a putative binding site for CCAAT/enhancer-binding protein beta (C/EBPbeta) (Akira et al., 1990). C/EBP transcription factors have been shown to promote or repress gene expression in the context of adult neuroplasticity, and learning and memory (Alberini et al., 1994, Menard et al., 2002), functions that are known to be affected by CB1R activation (Harkany et al., 2008).

Zhang and colleagues described a haplotype block in the intronic region upstream of exon 3 that consists of SNPs rs806379, rs1535255 and rs2023239 that has become increasingly interesting in relationship to several disorders (Zhang et al., 2004). In the original report, minor allele nucleotides were listed as T, A and G for the three SNPs in the order above. However, it is likely that the authors were using the minus strand rather than the plus strand of chromosome 6. The more standard convention is to use the plus strand, and by that convention the major/minor alleles for the three SNPs are: A/T, T/G and T/C (Lazary et al., 2009). Heterogeneity within this haplotype block is associated with significantly altered CNR1 mRNA expression; in particular the TGC (TAG) haplotype was associated with significantly lower CNR1 mRNA expression compared to the other combinations. (Zhang et al., 2004). In silico data analysis indicates that T alleles at both rs2023239 and rs1535255 results in the formation of specific binding sites for YY1 transcription factor that are not present when the minor alleles are expressed at these sites (Lazary et al., 2009). These data have lead to the hypothesis that the haplotype constructed from the three minor alleles (TGC) is associated with decreased CNR1 gene expression and, thus, decreased CB1R protein concentrations in brain (Lazary et al., 2009). However, post mortem brain samples from individuals with a C at rs2023239 (the third SNP in this haplotype block) exhibit significantly greater CB1R binding site density in prefrontal cortex compared to those homozygous for T (Hutchison et al., 2008), suggesting that the hypothesis needs further investigation.

Another SNP in the CNR1 regulatory region, rs806378, could also result in a change in transcription factor binding (Tiwari et al., 2010). The rare nucleotide at this SNP (T), but not the common (C), binds to arylhydrocarbon receptor translocator (ARNT). ARNT heterodimerizes with other transcription factors, including single minded 1 (SIM1) (Yang et al., 2004). The variable presence of a binding site for ARNT/SIM1 in the regulatory region of CNR1 could contribute to differences in CNR1 expression under some circumstances. Interestingly, there are associations with SIM1 and hyperphagic obesity in humans (Faivre et al., 2002) and the presence of a T allele at rs806378 is associated with obesity in French individuals (Benzinou et al., 2008). In addition, schizophrenic patients with a T allele at rs806378 gain more weight when treated with atypical antipsychotic agents (Tiwari et al., 2010).

Many other SNPs in the region of the CNR1 gene have been used as markers for genetic variation in CNR1 without any understanding at all of their functional consequences. This is a limitation of all gene association studies, but the incidence of significant correlations between CNR1 SNP genotypes and interesting and important phenotypes supports the need for studies that can elucidate their function.

2.2 Fatty acid amide hydrolase (FAAH)

2.3. Summary

In summary, heterogeneity in the human genes for both CB1R and FAAH have been identified and studied. While considerable progress has been made and there is clear evidence that they are both genetically polymorphic, critical basic questions about the functionality of the SNPs, particularly those in the CNR1remain.

3.1. Endocannabinoids are present in plasma and serum

The endocannabinoids can be measured in both plasma and serum. A side-by-side study found that AEA concentrations were 30% higher in serum than in plasma (Lam et al., 2010). In our experience, 2-AG can be measured more reliably and at higher concentrations in serum than plasma (Stuhr and Hillard, unpublished observations). Table 2 contains a list of studies in which plasma or serum endocannabinoid concentrations were determined in blood taken from healthy humans. AEA concentrations reported range from 0.4 to 13 nM; the majority of the studies reported mean concentrations between 1 and 5 nM. Approximately half of the investigations also measured the concentration of 2-AG; the range in this measure was 1-400 nM; the majority of studies reported mean 2-AG concentrations between 5 and 40 nM. When both AEA and 2-AG were measured in the same sample, 2-AG was usually, but not always, higher than AEA. Methodological and demographic differences among the studies likely explain the majority of the variance in endocannabinoid content. Within single studies, the standard deviations are typically less than 50% of the mean values for AEA; the variability in 2-AG is greater with standard deviations typically larger than 100% of the mean values.

Table 2

Plasma and serum concentrations of AEA and 2-AG in healthy, normal subjects

Like other circulating lipids, AEA can bind to albumin in the circulation (Giuffrida et al., 2000). Bovine serum albumin has one high-affinity binding site for AEA, with a Kd of 55 nM at 37°C (Bojesen and Hansen, 2003). Considering the data above that the concentrations of AEA in the circulation are in the range of 1-5 nM, it is likely that the majority of the AEA in the circulation is not bound. To our knowledge, the issue of 2-AG binding to albumin has not been examined.

3.2. Sources of circulating endocannabinoids

Since the endocannabinoids are synthesized by tissues and are lipophilic, movement in and out of tissues should be easily accomplished. Several studies support the notion that circulating concentrations of endocannabinoids are in equilibrium with concentrations in tissues. For example, the concentrations of AEA and 2-AG in brain microdialysates, which approximate their concentrations in the extracellular space of the brain, are approximately 2 and 5 nM, respectively (Caille et al., 2007). These concentrations are in the range of the concentrations of AEA and 2-AG in human serum and plasma. In a recent study, a nearly significant (p=0.0545) positive relationship was found between the concentrations of AEA in rat plasma and maternal tissues between days 8 and 19 of pregnancy (Fonseca et al., 2010). AEA is produced in the ovarian follicle during ovulation and peaks in the circulation at ovulation (El-Talatini et al., 2010). In addition to the brain and reproductive organs, significant amounts of endocannabinoids could enter the circulation from adipose tissues (Matias et al., 2006, Spoto et al., 2006). It is likely that liver clears the blood of endocannabinoids since both AEA (Caraceni et al., 2010b) and 2-AG (Westerbacka et al., 2010) are present at lower concentrations in the hepatic vein than in the rest of the circulation.

Another significant source of endocannabinoids in the serum and plasma are blood cells. Endocannabinoids are generated in blood, but not plasma, suggesting that blood cells synthesize and release endocannabinoids (Schmidt et al., 2006, Vogeser et al., 2006). In particular, macrophages (Varga et al., 1998,Di Marzo et al., 1999, Chouker et al., 2010) and platelets (Varga et al., 1998) release endocannabinoids when activated ex vivo by endotoxin and cytokines. Blood cells also have the capacity to inactivate AEA (Schmidt et al., 2006). This situation has practical as well as mechanistic implications because blood releases AEA in a temperature-dependent manner after harvest; as a result, AEA content can be dependent upon the time between the blood draw and time of plasma or serum separation (Vogeser et al., 2006). After separation of serum or plasma, AEA appears to be stable when stored frozen (Jian et al., 2010); the stability of 2-AG has not been thoroughly tested to our knowledge.

Human pathological conditions with a significant degree of inflammation or tissue injury are associated with significantly elevated plasma or serum endocannabinoids. Both AEA and 2-AG are both several times higher in serum from patients with endotoxic shock (Wang et al., 2001); AEA concentrations are higher in patients with cirrhosis (Fernandez-Rodriguez et al., 2004); and AEA is increased 3.5-fold and 2-AG 7-fold in patients with severe congestive heart failure (Weis et al., 2010b), a condition associated with systemic inflammation (Yndestad et al., 2006). Both AEA and 2-AG are detected in the synovial fluid of patients with arthritis, but not in healthy subjects (Richardson et al., 2008). Plasma 2-AG concentrations increase by several fold in patients undergoing cardiopulmonary bypass (CPB) compared to the same patients immediately after termination of the CPB; an effect that was suggested by the authors to be due to the inflammatory response evoked by this procedure (Weis et al., 2010a). Circulating 2-AG concentrations are increased in men with intra-abdominal adiposity (Bluher et al., 2006, Cote et al., 2007, Di Marzo et al., 2009a), a condition associated with a high degree of systemic inflammation (Marsland et al., 2010). Taken together, these data suggest the hypothesis that the synthesis of 2-AG, and perhaps also AEA, increases in blood cells and tissues in response to triggers of inflammation, which results in an increase of these lipids in the circulation.

Multiple studies have found that circulating endocannabinoids correlate with body mass index and are significantly increased in obese individuals. As mentioned above, 2-AG concentrations are increased in men with intra-abdominal adiposity (Bluher et al., 2006, Cote et al., 2007, Di Marzo et al., 2009a). Other studies have demonstrated significantly higher AEA concentrations in obese individuals (Sipe et al., 2010, Quercioli et al., 2011). Readers are referred to excellent reviews regarding endocannabinoids and metabolic disorders for further consideration of this topic (Di Marzo et al., 2011,Tam et al., 2011).

One interesting study has examined the correlation of circulating endocannabinoid concentrations with a series of descriptors that comprise the drug reaction scale (DRS) (McPartland et al., 2005). The DRS includes 67 descriptors categorized as indicators of perception, emotion, cognition, and sociability that was designed to discriminate between cannabinoid and non-cannabinoid drugs (Karniol et al., 1975). Serum endocannabinoid concentrations were determined in blood drawn from healthy subjects before and after osteopathic manipulations. Although the manipulation tended to increase serum AEA concentrations, the change did not reach statistical significance. However, significant correlations were observed between the changes in AEA and several DRS categories. In particular, the change in serum AEA concentrations was positively correlated with ratings of rational and cold and inversely correlated with ratings of paranoid and bad. These data suggest that AEA concentrations in the circulation might reflect mental state and mood in addition to physiological parameters.

3.3. Relationships between circulating endocannabinoids and stress

Exposure to psychological or physical threat evokes a repertoire of behavioral, endocrine and neuronal changes that heighten awareness, allow for a “fight or flight response”, and increase chances for survival should injury occur. Exposure to stress results in activation of the sympathetic nervous system, which is measured as an increase in heart rate and blood pressure. Stress also induces activation of the hypothalamic-pituitary-adrenal (HPA) axis, the ultimate result of this response is an increase in circulating glucocorticoid concentrations. Less well appreciated are the consistent and reproducible effects of stress to induce inflammatory responses in both the peripheral circulation and in the brain (Dantzer et al., 2008). In particular, acute psychological stress causes a transient elevation in the number of immune cells in the circulation as a result of activation of the sympathetic nervous system (Benschop et al., 1996). Specifically, monocytes are increased in the circulation following acute psychological stress (Bosch et al., 2003, Yamakawa et al., 2009) and exercise (Hong and Mills, 2008), both of which are accompanied by increased sympathetic activation. A meta-analysis of human studies examining the effects of acute psychological stress on pro-inflammatory cytokines found that an increased concentration of IL-6 at 90 min following acute psychological stress was the most consistently observed result (Steptoe et al., 2007). A recent, comprehensive study of the effects of the Trier Social Stress Test (TSST) on a variety of cytokines demonstrated an immediate effect of stress exposure to increase natural killer T cells and the concentrations of interleukin 1beta (IL-1β) in male subjects (Yamakawa et al., 2009). The authors of this paper present the hypothesis that sympathetic activation results in a rapid migration of monocytes and macrophages into the circulation; these cells are also triggered by the sympathetic nervous system to release some cytokines, including IL-1β.

There are several places where endocannabinoid signaling and the three stress responses described intersect. First, endocannabinoid/CB1R signaling regulates the HPA axis response at multiple sites, including the hypothalamus (Di et al., 2003); pituitary (Yasuo et al., 2010) and adrenal gland (Ziegler et al., 2010b). CB1R activation at these sites inhibits HPA axis activation. Within the CNS, endocannabinoid signaling in the amygdala gates the activation of the HPA axis by stress (Hill et al., 2009b) and activation of endocannabinoid/CB1R signaling in prefrontal cortex is required for appropriate recovery of the HPA axis to baseline following stress offset (Hill et al., 2011).

Second, CB1R are present on sympathetic nerve terminals and their activation results in decreased norepinephrine release (Ishac et al., 1996). Therefore, increased endocannabinoid tone at these receptors would result in decreased sympathetic responses.

Third, CB1R signaling is required for appropriate brain stem regulation of sympathetic responses via the baroreflex. The baroreflex is a feedback mechanism triggered by activation of mechanoreceptors, called “baroreceptors” in arteries. Activation of the baroreceptors results in inhibition of sympathetic outflow and, thus, reduces pressure in the vasculature. Sympathoinhibitory responses to activation of the baroreceptor reflex are enhanced by endocannabinoid signaling in the nucleus tractus solitarius (NTS) (Seagard et al., 2004, Seagard et al., 2005, Chen et al., 2010). This mechanism is also consistent with endocannabinoids opposing or buffering stress responses.

Fourth, as was discussed in 3.2., endocannabinoids are released from circulating monocytes and macrophages. Both CB1R and a second subtype of cannabinoid receptors, CB2R, are expressed by immune cells and their activation is generally found to inhibit cytokine secretion and activation (Carrier et al., 2005). In particular, the ability of LPS to increase plasma IL-1β concentrations is inhibited by CB1R agonists (Roche et al., 2006). A study carried out in humans demonstrated that plasma concentrations of 2-AG and the cytokine, tissue necrosis factor alpha, are significantly negatively correlated (Koppel et al., 2009). Taken together, the available data supports the hypothesis that activated immune cells secrete endocannabinoids, which in turn, inhibit the secretion of some cytokines. Thus, the effects of the endocannabinoid system on immune system can also be characterized as stress buffering or enhancing stress recovery.

The effects of various physiological and psychological stressors on circulating endocannabinoids have been determined in humans and most studies find that endocannabinoids are increased by stress. Although our understanding of the sources and targets of the endocannabinoids in the circulation is still very incomplete, it is our working hypothesis that stress-responsive endocannabinoids enter the circulation from either the brain or circulating immune cells. Furthermore, we hypothesize that they function to dampen the initial stress response or serve a recovery role.

Several studies support the hypothesis that endocannabinoids, particularly 2-AG are increased by stress in parallel with the occurrence of an overall pro-inflammatory state. In a study of endocannabinoid responses to surgical stress, 2-AG concentrations were found to increase significantly after the start of cardiac surgery and were increased 3 fold during cardiopulmonary bypass procedure (Weis et al., 2010a). Furthermore, 2-AG concentrations were significantly, positively correlated with IL-6 concentrations in this study. Hemodynamic stress elicited by being held for 30 min (or until syncopal symptoms occurred) at 70° in a head up tilt resulted in significantly increased 2-AG concentrations compared to those obtained in the supine position (Schroeder et al., 2009). Although this study did not examine any parameters of inflammation or immune activation, previous studies have found that head up tilt procedures result in a transient increase in NK cell number that is driven by sympathetic activation (Klokker et al., 1997). However, no correlations between 2-AG and any marker of sympathetic activation were observed in the orthostatic stress study (Schroeder et al., 2009) which is in opposition with our hypothesis in its current form.

In another study, parabolic flight maneuvers were used to stress human volunteers and blood endocannabinoid contents, cortisol and motion sickness were the measured outcomes (Chouker et al., 2010). The results of this study support the hypotheses that circulating endocannabinoids can be affected by stress; interestingly AEA concentrations increased earlier, during the stress itself while 2-AG increased later and were more closely related to the recovery phase. A study by the same group using the same parabolic stress protocol found that polymorphonuclear cell concentrations were increased in blood immediately after the parabolic flights (Kaufmann et al., 2009b).

Another theme that emerges when these three studies are considered together is that endocannabinoid concentrations are inversely related to the severity of stress-induced sequelae. In the parabolic flight stress study (Chouker et al., 2010), AEA concentrations in the circulation decreased in subjects who developed motion sickness and increased in those who did not. Similarly, 2-AG concentrations did not change significantly in those with motion sickness but increased in those who did not experience motion sickness. Cortisol concentrations were significantly, inversely correlated to AEA concentrations across all subjects. Interestingly, the circulating concentrations of both AEA and 2-AG in flight but before the parabolas occurred were higher in the group that would not experience motion sickness; this could be evidence of differences in stress responsivity in general between high and low endocannabinoid response groups.

Although the concentration of AEA in the circulation was unchanged by the orthostatic stress in the head up tilt study (Schroeder et al., 2009), circulating concentrations of AEA were significantly, positively correlated with orthostatic tolerance. Furthermore, individuals with AEA concentrations above the median exhibited a significant, rightward shift in the relationship between tilt-angle and increased heart rate. AEA concentrations did not correlate with changes in blood pressure. Therefore, although stress did not affect AEA, the basal concentration of AEA affected the reflex responses to the orthostatic stress. One explanation for these data is that individuals with high AEA could have a blunted sympathostimulatory response to unloading of the baroreceptors. Interestingly, in the cardiac surgery study, AEA concentrations were significantly positively correlated with the amount of norepinephrine required to maintain vasomotor tone (Weis et al., 2010a), which is also consistent with this explanation. As was discussed in section 3.3 above, high AEA tone in the NTS is associated with sympathoinhibition (Seagard et al., 2004), so perhaps the circulating AEA reflects AEA signaling in the NTS. Alternatively, high circulating AEA could inhibit sympathetic tone at the level of the sympathetic terminals through CB1R-mediated inhibition of norepinephrine release (Ishac et al., 1996).

Our laboratory has carried out a study of the effects of psychological stress on serum endocannabinoid concentrations in women (Hill et al., 2009c). A seventeen-minute version of the TSST resulted in a significant increase in 2-AG concentrations that returned to basal concentrations 30 min after the end of the stress. Serum AEA concentrations were not significantly different from baseline at either time point. Similarly, a study in which imagery of a previous stressful experience was administered, AEA concentrations were not changed from baseline but slowly dropped until they were significantly lower than baseline 75 min after the end of the stress (Mangieri et al., 2009). As was mentioned above, the TSST has also been shown to result in increased blood monocyte and cytokine concentrations (Yamakawa et al., 2009). A hypothesis that should be tested is whether the changes in 2-AG during the TSST are correlated with cytokines, particularly IL-1β and IL-6.

3.4. Summary

The concentrations of endocannabinoids in the circulation have informational content. There is evidence that endocannabinoid concentrations in the circulation and brain are in equilibrium and, in women, also reflect concentrations in reproductive tissues. There is also evidence from multiple diseases that AEA and, to a greater degree, 2-AG concentrations are increased in the circulation when the immune system is activated during inflammation, infection or injury. The hypothesis that circulating endocannabinoids are related to their concentrations in brain makes them attractive biomarkers of CNS endocannabinoid tone. However, this notion is complicated by the fact that other tissues also donate endocannabinoids to the circulation, so that a brain biomarker function could be masked by changes in endocannabinoid homeostasis in other tissues or within the immune system. In spite of these caveats, currently available data indicate that circulating endocannabinoid measures, particularly during stressful experiences, could serve as a biomarker for several aspects of the vulnerability to stress-induced sequelae.

4.1. Associations of heterogeneity in CNR1 and FAAH with CNS function in healthy controls

Mental diseases are very complex in the constellation of symptoms that occur, are heterogeneous in their etiology and exhibit large individual differences in treatment outcomes. The purpose of this section is to examine the evidence that heterogeneity in endocannabinoid signaling could contribute the symptoms, etiology or treatment success of several important mental diseases. There is also evidence that genetic heterogeneity of CNR1 and FAAH could add further variability to these diseases, and to normal variability in the population, affecting basic processes such as personality, reward sensitivity or fear processing. These data will be discussed first.

4.2. Substance Use Disorders

CB1Rs are found in human brain regions associated with reward processing, including the ventral tegmental area, the nucleus accumbens, and prefrontal cortex (Glass et al., 1997). Activation of CB1Rs is rewarding in animals (Gardner, 2005, Solinas et al., 2008) and CB1R antagonists reduce the rewarding effects of drugs of abuse such as opiates, nicotine, alcohol, and cocaine, indicating that the endocannabinoid system is involved in the neurobiological mechanism underlying substance abuse (De Vries et al., 2005, Maldonado et al., 2006). Administration of the CB1R antagonist, rimonabant, to healthy subjects reduced the neural response to the sight and taste of chocolate in key reward areas such as the ventral striatum and the orbitofrontal cortex, and increased lateral orbitofrontal activation in response to the sight and taste of molding strawberries, an aversive stimulus (Horder et al., 2010).

The development of a substance use disorder is a step-wise progression from initial use to regular use to dependence. There is evidence that environmental and genetic factors are involved in the progression. In a recent review of the genetics of substance abuse, Bierut suggested that dependence should be considered a pharmacogenetic disorder to which many diverse genes contribute (Bierut, 2011). In light of the role of endocannabinoid signaling in the regulation of reward, many studies have been carried out to examine the hypothesis that genetic heterogeneity in endocannabinoid signaling contributes to the likelihood an individual will develop a substance use disorder.

4.3 Depression

Humans have used cannabis sativa for thousands of years for a variety of reasons, including to elevate mood. In a study of young, poly-substance users, 69% of the respondents reported that they used cannabis to “make themselves feel better when down or depressed” (Boys et al., 2001). These results suggest that some users of cannabis are self-medicating a depressed mood with the drug. However, evidence indicates depressed subjects actually experienced more depression, aggression and sadness when intoxicated with cannabis than when they are not intoxicated (Arendt et al., 2007). Heavy cannabis use and major depression are co-morbid in clinical and community populations (Degenhardt et al., 2003, Lynskey et al., 2004) and several prospective studies have found that cannabis use precedes the diagnosis of depression (Bovasso, 2001, Patton et al., 2002, Rey and Tennant, 2002). However, a large (greater than 12,000 participants) longitudinal study did not find that past cannabis use was a significant predictor of depression in adults when baseline differences between users and non-users were carefully controlled (Harder et al., 2006). Therefore, neither the evidence that cannabis treats depression nor the evidence that cannabis use causes depression is convincing.

However, Harder and colleagues suggested, based upon the their longitudinal results, that a shared genetic predisposition could underlie the association of depression and cannabis use (Harder et al., 2006). In support of this hypothesis, several recent studies have demonstrated that the genetic factors for cannabis dependence and depression/suicidality are moderately correlated (Fu et al., 2002, Lynskey et al., 2004). Twin studies suggest that shared environmental factors also contribute significantly to the co-morbidity of cannabis dependence and depression (Lynskey et al., 2004).

While THC from cannabis and the endocannabinoid system have in common the CBR1, the effects of cannabis use do not necessarily match the role of the endocannabinoid system. This could be due, in part, to the fact that THC is a partial agonist of the CB1R (Kearn et al., 1999); therefore, THC can produce CB1R agonist effects when endocannabinoid tone is low and antagonist-like effects when endocannabinoid tone is high (Roloff and Thayer, 2009). With regard to a role in depression, data from the clinical experience with the CB1R antagonist, rimonabant, suggest that endocannabinoid/CB1R signaling contributes to maintaining a non-depressed mood. A significant occurrence of depressed mood was found in patients given the CB1R antagonist, rimonabant, for weight loss and obesity-related metabolic disorders (Christensen et al., 2007,de Mattos Viana et al., 2009). As was mentioned in section 4.2, CB1R inhibition reduces the hedonic aspects of sight and smell, which is consistent with a role of endocannabinoid signaling in hedonic processing (Horder et al., 2010).

In further support for a role for the endocannabinoid system in depression, Hungund and colleagues examined CB1R binding site density and ability to signal in post mortem samples from subjects with major depression who died by suicide (Hungund et al., 2004). They found that depressed suicides had 24% greater number of CB1R agonist binding sites and significantly more CB1R protein on western blot in prefrontal cortex than matched controls. Depressed suicides also have increased cannabinoid agonist-evoked GDP/GTP exchange, evidence that the increased receptors are functional. These data are supported by preclinical findings that chronic unpredictable stress in rats (a paradigm that results in symptoms of anhedonia, behavioral inflexibility and hyperactive HPA axis responsivity) also increases CB1R binding site density (Hill et al., 2008a) and CB1R mRNA expression (Bortolato et al., 2007) in prefrontal cortex. On the other hand, chronic unpredictable stress models in rodents decrease CB1R density in subcortical regions, including the hippocampus (Hill et al., 2005, Hill et al., 2008a), suggesting that a shift in the balance of endocannabinoid signaling between cortical and subcortical regions could contribute to depression.

Repeated exposure to stress can have negative consequences on humans and is a contributing factor for several mental disorders. However, most people are resilient to the effects of stress and the biological processes that underlie stress resilience are beginning to be understood (Feder et al., 2009). Among the resilience factors are several psychobiological factors that are associated with a high level of CB1R activation in preclinical studies, including: a low amount of fear-generalization; dampened hypothalamic-pituitary-adrenal axis activation by acute stress; use of active coping strategies; and high reward responsivity (Hill et al., 2010b). As was discussed in section 4.1, carriers of FAAH 385A have decreased threat-related amygdalar reactivity and increased reward-related activation of the ventral striatum (Hariri et al., 2009).

4.4. Anxiety and eating disorders

The most commonly cited reasons for continued recreational cannabis use are relaxation and reduction in tension (Thomas, 1993, Reilly et al., 1998, Schofield et al., 2006). Paradoxically, the most commonly cited reasons for discontinuation of cannabis use are increased anxiety and panic reactions (Szuster et al., 1988,Reilly et al., 1998). Modulation of anxiety reactions by cannabis appears to be complex in that both dose and environmental context can modulate these effects. Subjects under “experimenter harassment” were more likely to experience anxiety reactions under the influence of cannabis than those in neutral environments (Gregg et al., 1976).

Psychiatric adverse effects, including anxiety, were cited as reasons for discontinuation by patients taking rimonabant significantly more than those taking placebo (Van Gaal et al., 2008), although objective measures of anxiety were not significantly increased in patients taking rimonabant (Scheen et al., 2006). A recent meta-analysis pooling data from four large clinical trials indicated that subjects taking rimonabant had a significantly greater increase in anxiety symptoms while taking the drug than patients taking placebo (Christensen et al., 2007). Therefore, human experience with a CB1R agonist (THC) and antagonist (rimonabant) support the hypothesis that endocannabinoid signaling regulates anxiety in humans and suggest that activation of the CB1R by endocannabinoids could produce anxiolytic effects.

Posttraumatic stress disorder (PTSD) occurs in about 30% of individuals following exposure to an extreme traumatic stressor. At the time of the stress exposure, the person’s response is intense fear, helplessness or horror. The disorder includes a set of characteristic symptoms including persistent, intrusive recollections or re-experience of the original event, numbing and avoidance and increased arousal (2000). Anecdotal reports of cannabis use causing relief of PTSD symptoms by returning veterans are abundant. A recent, systematic study demonstrated that PTSD diagnoses were associated with increased odds of lifetime history of cannabis use as well as past year daily cannabis use (Cougle et al., 2011). As for other disorders that are associated with heavy cannabis use, the mechanistic relationships between PTSD risk and cannabis use are not known. A small study of the therapeutic benefit of nabilone, an CB1R agonist that is given orally, a majority of patients treated (72% of 47 patients total) experienced a significant reduction in intensity or complete elimination of nightmares (Fraser, 2009). However, this study was not placebo controlled and needs to be confirmed with larger, better-controlled studies.

4.5. Schizophrenia

Schizophrenia is the second most common mental illness after depression. It usually begins in late adolescence or early adulthood. Symptoms include delusions or hallucinations; loose association; blunted or inappropriate affect and distortion of perceptions. A number of case reports indicate that consumption of large amounts of cannabis with high THC content can result in “cannabinoid psychosis”, with many similarities to schizophrenia (Ujike and Morita, 2004). Cannabis use in adolescence imposes a two-fold increased risk for the development of schizophrenia (Arseneault et al., 2002, Zammit et al., 2002). Meta-analyses estimate that adolescent cannabis use may account for 8-14% of schizophrenia cases (Henquet et al., 2005, Jiang et al., 2007, Moore et al., 2007). Taken together, these studies suggest that excessive activation of CB1R signaling could contribute to the etiology of schizophrenia.

Several studies have examined the density of CB1R in post mortem human brain. Autoradiographic studies have demonstrated that CB1R binding site density in the dorsolateral prefrontal cortex (Dean et al., 2001) and cingulate cortex (Zavitsanou et al., 2004, Newell et al., 2006) of schizophrenics compared to controls. This finding was confirmed in living humans (Wong et al., 2010) using a PET radioligand, [11C]OMAR, which has high selectivity for the CB1R (Horti et al., 2006). In particular, this study demonstrated increased CB1R density throughout the brain in schizophrenics compared to controls, reaching significance only in the pons. On the other hand, no difference in the density of neurons expressing CB1R in the anterior cingulate cortex was observed in an immunohistochemical study (Koethe et al., 2007). Furthermore, a comprehensive and well executed study by Eggan and colleagues demonstrated that CB1R mRNA and CB1R immunoreactivity were significantly lower in GABAergic neurons in the dorsolateral prefrontal cortex of schizophrenics compared to controls (Eggan et al., 2008). Based on the roles of CB1R and GABAergic transmission in the dorsolateral prefrontal cortex, these authors hypothesized that reduced CB1R inhibition of GABA release could serve as a compensatory mechanism to increase GABAergic transmission, which is impaired in schizophrenia (Lewis et al., 2005).

4.8 Attention deficit disorder

The data discussed in section 4.1.2. suggest a role for the endocannabinoids in attention deficit/hyperactivity disorder (ADHD). Specifically, several SNPs and the length of the AAT repeat in one ethnic group exhibit significant relationships with measures of impulsivity (Ehlers et al., 2007) and individuals with an A allele at FAAH 385 exhibit more impulsivity in the delay discounting task (Hariri et al., 2009). Two studies have examined this issue directly. In the first, FAAH activity was found to be lower in peripheral lymphocytes of boys diagnosed with ADHD than matched controls (Centonze et al., 2009). Although genotype was not determined in this study, these data are in accord with the finding that subjects expressing FAAH 385A, which results in reduced FAAH protein expression (Chiang et al., 2004). The second study examined the contribution of CNR1polymorphisms of two, two-SNP haplotype blocks (rs806368/rs1049353 and rs806377/rs6454574) that fall into haplotype blocks 2 and 1, respectively, in Table 1 (Lu et al., 2008). A significantly increased risk for ADHD was associated with a C/G genotype at rs806377/rs6454574; none of the other combinations were significantly associated. The association was gender-dependent, contributing more strongly to risk in males than females. Interestingly, there were no significant associations of ADHD with the other haplotype block examined (rs806368/rs1049353), in contrast to the finding that both of these SNPs were associated with impulsivity in another study (Ehlers et al., 2007).

ADHD, in addition to impulsivity, also involves emotional dysregulation and there is evidence to support increased amygdalar reactivity (Plessen et al., 2006); differences in prefrontal-limbic circuitry (Durston et al., 2006) and poor HPA axis responsivity (King et al., 1998) in individuals with ADHD compared to controls. Taken together with the data above, it is possible that the role of endocannabinoid signaling in the regulation of stress responses and emotional regulation underlies its contribution to ADHD risk.

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