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Page 1 of 11 A Review of the Relationship between the and the Reduction of Depression and 2019

A Review of the Relationship between the Endocannabinoid System and the Reduction of Depression and Anxiety

Ashorne Krithiesh Mahenthiran Northwestern University, Evanston, Illinois 60201

The growing acceptance of use for medical and recreational purposes across the world has sparked interest in evaluation of the therapeutic potential of the . While the beneficial use to treat physical pain are well-known, its efficacy as a treatment for mental disorders has not been as extensively investigated. As the most prominent and widespread of these disorders, depression and anxiety have been diagnosed in individuals across the world. Despite the wide range of severity for these disorders, tricyclic and selective reuptake inhibitors are predominately prescribed to treat any case. However, these compounds are not always effective treatments, which leaves a need to investigate alternative treatment options for depression and anxiety. This review article aims to identify prominent studies focused on evaluating the potential of the human endocannabinoid system, which consists of two main subtypes (CB1 and CB2). Prior studies have focused on the use of exogenous such as or phytocannabinoids such as delta-9- THC, but this review gives more consideration to endocannabinoids that are produced by the human body. In addition to experiments testing the independent capacity of endocannabinoid receptor ligands as antidepressants, the additive and synergistic potentials of these ligands have been examined in conjunction with cholinergic receptor ligands through the use of mice FST. Recent studies have also indicated that certain genetic variants within the endocannabinoid system such as the CB1 rs1049353 G allele have been linked to increased prevalence of mental health disorders and provide a rationale for gender discrepancies in disorder incidence. Although current research into the prospective use of endocannabinoids as antidepressants is limited, this review details the field’s most salient advancements toward potential clinical applications.

Abbreviations: CB1 – type 1; CB2 – cannabinoid receptor type 2; delta-9- THC – delta-9-tetrahydrocannibinol; CBD – ; FST – forced swim test

Keywords: Neuropsychopharmacology; CB1 receptor; CB2 receptors; SSRIs; TCAs; Cannabis; Endocannabinoids; Phytocannabinoids; Depression; Anxiety; Cholinergic receptors

Introduction Across the world, depression affects twice as likely to develop depression when individuals from different ages, ethnicities, and compared to males and approximately twenty socioeconomic classes. This condition can range percent of the world’s population has the in severity from increasing an individual’s condition for some period during their lifetime. reclusiveness to causing severe disruptions in an Additionally, the recurrence of depression after individual’s daily life, sometimes resulting in recovery exacerbates the risk of cardiac disease fatal suicide attempts. The disease is difficult to and other psychiatric disorders (Brigitta, 2002). diagnose because symptoms are difficult to Anxiety, like depression, has emerged in a sizable measure and there are many distinct disorder portion of the ’ population (over 13 subtypes (Brigitta, 2002). Females are generally percent) and also has its own set of debilitating Page 2 of 11 A Review of the Relationship between the Endocannabinoid System and the Reduction of Depression and Anxiety 2019 symptoms. Specifically, anxiety has been linked pathways that are affected in patients for possible to increases in unproductivity, drug abuse, and treatment. even mortality rates, which often persist due to The predominant biological theory for lack of individualized management beyond a depression and other affective disorders is the primary care provider (Bystritsky, 2013). The monoamine hypothesis. Monoamines, including ubiquitous nature of depression and anxiety as serotonin and , stimulate G protein- well as their correlation to potentially fatal health linked receptors on postsynaptic to outcomes has sparked research efforts to identify respond to neurotransmitters responsible for risk factors and understand their biological basis. affecting brain responsiveness (Kalia, 2005). This review manuscript aims to provide an in- Pharmacologically, the monoamine hypothesis depth overview of research on the has been supported, as reserpine-like that endocannabinoid system as a treatment option to deplete monoamines have been found to promote improve the health outcomes of individuals with depression. Also, the brains of suicidal mental disorders. individuals had levels of serotonin (5-HT) Research has outlined that depression content that were comparable to controls (Kalia, emerges from a dynamic combination of stressful 2005). The identification of low serotonin levels life events and genetic predispositions that is being correlated to depression has influenced the specific to each patient. Stressful life events have types of drugs that have been manufactured to been repeatedly found to increase depressive treat the condition. symptoms in adults and children, which has led Tricyclic antidepressants (TCAs) and to the development of the stress sensitization monoamine oxidase inhibitors (MAOIs) were the hypothesis that “subsequent episodes [of primary option for the treatment of depression, depression] require less stress to elicit a until the more recent development of selective depressive recurrence” (Shapero et al., 2014, 2). serotonin reuptake inhibitors (SSRIs) and The stress sensitization hypothesis has been serotonin- reuptake inhibitors supported in cases where childhood emotional (SNRIs). While these compounds have the same abuse is the stressful life event, as these basic biological mechanism involving the individuals exhibited more symptoms of “inhibition of reuptake of monoamine depression during adulthood than the general neurotransmitters from the synaptic cleft,” TCAs population (Shapero et al., 2014). Thus, it is and MAOIs have distinct “degrees of direct known that life events have a role in causing receptor antagonist activity” that cause them to depression, but it is difficult to quantify the have more detrimental side effects (Bodkin et al., correlation between the stress of an event and the 2007). SSRIs have been developed to have less severity of the condition. hazardous side-effect profiles and higher Depression has a projected heritability of serotonin specificity than the traditional TCAs; sixty percent, revealing that genetics are likely to this has led to them being prescribed more often have an influence on the conditions’ emergence by physicians (Sangkuhl et al., 2009). SSRIs, (Wang et al., 2015). In addition, genetic regions however, are more expensive to produce and have emerged that appear to deviate solely in administer than TCAs. Furthermore, meta- patients with depression conditions, such as the analyses revealed there was negligible difference T-182C polymorphism in the “5’ promoter and in efficacy and side effects between the two coding region of the norepinephrine transporter classes (Anderson, 2000). In the case of anxiety (NET) gene” (Wang et al., 2015, 4). Experiments treatment, SSRIs and SNRIs are also the most that have attempted to identify genetic loci commonly administered classes of medications. responsible for the onset of depression never However, the effectiveness of SNRIs largely reach a consensus, which elucidates the varies based on the patient case and SNRI complexity of depression as a preventable treatment can even result in a worsening of condition. Given the difficulty of managing the physiological symptoms (Bystritsky, 2013). risk factors for depression, most research has These findings reveal that SSRIs and SNRIs may instead focused on understanding the biological not have been as revolutionary a development in Page 3 of 11 Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences 2019 the treatment of depression or anxiety as more direct biological evidence that these previously hoped. receptor subtypes might be involved in the Another issue complicating the treatment development of depression as well. Studies have of depression and anxiety is the existence of indicated that CB1 and CB2 receptors genetic patient cases where the condition is unresponsive polymorphisms have been associated with to treatment with conventional TCAs or SSRIs. depression and even treatment resistance in some In these cases, physicians have switched the type depression patients (Huang et al., 2016). of TCA or SSRI being used, but the response to Although cannabis has been mostly restricted to this switch is limited. The maximum increase in a recreational context because of existing stigma, patients’ improved response was twenty-seven behavioral mice studies revealed that their coping percent when switching between TCA mechanisms for fear and stress involved compounds and seventy-five percent when upregulation of their endocannabinoid system switching between SSRI compounds (Tundo et (Alger, 2013). This biological evidence of the al., 2015). While these two classes may treat most endocannabinoid system being altered in patients cases of depression, there exists a need for the with depression and behavioral evidence of the discovery and production of a therapeutic endocannabinoid system being involved in the alternative. extinction of stress validates investigation into The endocannabinoid system has whether endocannabinoids and/or exogenous demonstrated some potential to be a novel target cannabinoid ligands can act as effective for the development of this alternative. In order antidepressants. to further understand the novelty of using There are two primary endocannabinoids endocannabinoids as antidepressants, it is identified in the human body, and 2- important to differentiate between exogenous arachidonyl glycerol, whose role as ligands in the cannabinoids, phytocannabinoids, and endocannabinoid system have been studied endogenous cannabinoids (endocannabinoids). extensively. Anandamide has unique properties Exogenous cannabinoids refer to any in that its concentration determines the number of cannabinoid compound that originates outside of receptors that are activated and that it can both the human body and includes those that are make and destroy short-term neuronal pharmaceutically manufactured or stem from connections related to memory (Sallaberry and plants (phytocannbinoids). Contrarily, Astern, 2018). Although anandamide is endocannabinoids refer to cannabinoid considered to have analgesic potential because of compounds that originate from the human body. its high affinity for CB1 receptors, this affinity There are currently two known subtypes and its role in memory have led to its of cannabinoid receptors in the human body: CB1 consideration for the treatment of psychological and CB2 receptors (Kruk-Slomka et al., 2015). disorders like post-traumatic stress disorder CB1 receptors are the more abundant subtype and (PTSD) (Sallaberry and Astern, 2018). These are concentrated in the central nervous system properties of anandamide further lend support to (CNS), especially the limbic system and brain the mice study mentioned earlier in which the areas associated with emotion (Kruk-Slomka et endocannabinoid system has been identified as al., 2015). Contrarily, CB2 receptors are mostly part of the coping mechanism to deal with anxiety found in peripheral tissues of the immune system, or depression. 2-arachidonyl glycerol (2-AG) is but have also been discovered to exist in the the most prevalent endocannabinoid present in cerebellum and the hippocampus (Kruk-Slomka the human body, but unlike anandamide it is et al., 2015). Both receptor subtypes belong to the considered both a CB1 and CB2 receptor same class of G-protein coupled receptor that with a more prominent role in anti-inflammation regulates the release of neurotransmitter when as part of the human immune response stimulated (Huang et al., 2016). The location of (Sallaberry and Astern, 2018). Although both of these receptor subtypes and their mechanism of these endocannabinoids have the ability to action involving neurotransmitter inhibition have stimulate cannabinoid receptors, their relevance created speculation that they could be involved in in preventing the uptake of serotonin and acting the treatment of depression. There has also been as antidepressants is still being explored. Page 4 of 11 A Review of the Relationship between the Endocannabinoid System and the Reduction of Depression and Anxiety 2019 While the endocannabinoid system has studies have focused on understanding the role of shown potential to be involved in the treatment of these receptors in the reduction or treatment of depression, there have been studies depicting depression and anxiety. In this section, some of cannabis use as a cause of depression rather than these studies will be evaluated to provide a more a treatment. A longitudinal study conducted in thorough understanding of how relevant the New Zealand revealed that increased cannabis endocannabinoid system is to the manufacturing usage between the ages of fourteen and twenty- of cannabinoid receptor-based antidepressants. one was associated with statistically significant reductions in reported satisfaction with life, CB1 Receptor and Antagonists’ which is a common symptom of depression Effects on Anxiety (Fergusson and Boden, 2008). This illustrates a In 2006, a study at the Medical College lasting effect of cannabis on brain chemistry of Wisconsin evaluated the effects of direct and beyond the period of frequent ingestion as indirect CB1 receptor agonists and antagonists on depression was still observed at a later stage in anxiety-related behaviors in mice using the life. Although this study could be criticized for its elevated-plus maze paradigm. This study was qualitative nature, other experiments have found particularly noteworthy because it deviated from that acute administration of delta-9- solely testing the exogenous cannabinoids that (THC), the main had been the focus of previous studies. Instead, psychoactive component of cannabis and a CB1 the study used multiple drugs belonging to each receptor agonist, increased “subjective ratings of class of agonist and antagonist with a range of anxiety” and led to a “greater response to fearful doses to evaluate the role of endocannabinoid than to neutral faces” (Bhattacharyya et al., 2017, signaling in mediating anxiety. The mice were 6-12). These studies pose a threat to the viability housed in treatment groups of up to ten mice, of endocannabinoids being used as substitutes for each mouse was tested once in the elevated-plus antidepressants because they reveal CB1 receptor maze. The design of the maze consisted of a agonists that have caused symptoms regularly central platform with two open and two enclosed associated with depression. However, the arms extending off the platform (Patel and administration and dosing of endocannabinoids Hillard, 2006). The percentage of time spent in that would be designed as antidepressants varies open arm exploration was the primary indicator significantly from the recreational conditions in of reduced anxiety, but percentage and number of the longitudinal study and the acute conditions of open arm entries (four paws placed on the the delta-9-THC study. Given the possibility that platform) were also measured as indicators of endocannabinoid system may provide an reduced anxiety. Contrarily, closed arm alternative treatment options for depression and exploration along with percentage and number of anxiety, the conflicting results from existing closed arm entries were measured to be markers studies warrant extensive research to unearth of anxiety-like behaviors (Patel and Hillard, whether there is therapeutic potential. 2006). The two CB1 receptor agonists selected State of the Field: Investigating the for the study significantly increased the Endocannabinoid System percentage of time spent in open arm exploration. As the stigma surrounding use CP 55,940, an effective CB1 receptor agonist, for medicinal purposes has decreased over the increased all three components of open-arm last couple decades, research has focused on exploration that were deemed to be associated examining the use of both endocannabinoids and with reduced anxiety. Furthermore, this exogenous, for the reduction in anxiety was visible at almost all treatment of diseases ranging from Alzheimer’s concentrations across the dosing range (Patel and disease to cancer. Since the CB1 and CB2 Hillard, 2006). These findings were replicated by receptor subtypes of the endocannabinoid system another high-efficacy agonist, WIN 55212-2, at have been found to have a role in CNS areas dosages of 1 and 3 mg/kg, but were not supported associated with emotion, many of these research by treatment of the mice with THC across all Page 5 of 11 Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences 2019 dosages (Patel and Hillard, 2006). Expectedly, temperature and locomotor activity was a vital both of the CB1 receptor antagonists AM251 and control because it determined the doses of SR141716, had an adverse effect on anxiety-like treatments that caused hypothermia or catalepsy, behaviors. At 3 and 10 mg/kg of both drugs, the respectively. These doses were subsequently time spent in open arm exploration was removed prior to testing via the FST or TST (El- significantly decreased, which indicates the Alfy et al., 2010). The FST consisted of the mice promotion of anxiety-like behaviors (Patel and being placed in a cylinder filled with water, and Hillard, 2006). Finally, the study tested the then measuring subsequent locomotor activity effects of pharmacological augmentation on and immobility. The TST involved hanging mice endocannabinoid signaling through the use of by the tail after treatment and then measuring the two modulators: URB597 and AM404. At 0.1 time each mouse spent motionless (El-Alfy et al., and 0.3 mg/kg of URB597 along with 1 and 3 2010). In the FST and TST, locomotor activity mg/kg of AM404, there was a significant increase was classified to be a marker of anti- in time spent in open arm exploration that was activity and immobility was a marker of a similar to the effects of the high-efficacy CB1 depressed state. receptor agonists (Patel and Hillard, 2006). This As expected, both the TCA desipramine study shows a statistically significant dichotomy and the SSRI caused significant in anxiety-like behaviors between CB1 receptor decreases in FST immobility times. While delta- agonists and antagonists. However, there does 9-THC and delta-8-THC revealed non-significant seem to be some importance regarding the reductions in immobility, CBD and CBC caused structure and type of receptor being used, a significant reduction in mice immobility, which as THC failed to decrease anxiety-like behavior. suggests that these compounds have Furthermore, this study’s finding that the potential (El-Alfy et al., 2010). augmentation of endocannabinoid signaling is Both CBG and CBN failed to cause significant sufficient for significant reduction of anxiety-like change in mice locomotor activity in the FST behavior proposes another mechanism of when compared to the control, which weakens treatment that may be effective in humans. their potential to act effectively as antidepressants. In the TST, delta-9-THC and Phytocannabinoids Act on Endocannabinoid CBC caused a significant decrease in immobility System as Antidepressants time, but none of the compounds caused a Since most research studies focus on the significant change in locomotor activity (El-Alfy evaluation of synthetic CB1 ligands for anti- et al., 2010). The highly predictive nature of the depressant action, researchers at the University of FST and TST procedures underscores that certain Mississippi focused their 2010 study on phytocannabinoids have the potential to cause elucidating the role of phytocannabinoids like antidepressant action. Specifically, delta-9-THC delta-9-THC, delta-8-THC, cannabidiol (CBD), and CBC were successful in reducing immobility (CBG), (CBN), and in both procedures, which entails further (CBC) that are more investigation into the antidepressant potential of commonly found in the types of cannabis these compounds. Even though delta-8-THC ingested by recreational users. In this study, these behaved similarly to delta-9-THC in the mouse phytocannabinoids were obtained from potent tetrad assay, delta-8-THC did not demonstrate , and tested alongside anti-depressant effects at any dose. A significant desipramine and fluoxetine hydrochloride for difference between delta-8-THC and delta-9- comparison to TCAs and SSRIs (El-Alfy et al., THC is their binding affinity for the CB1 2010). Eight-week-old mice were injected receptor; in-vitro assays have revealed that delta- intraperitoneally with either a vehicle control or 8-THC’s binding affinity is three-fold lower than the assigned dosage of a test compound prior to delta-9-THC (El-Alfy et al., 2010). Thus, an participation in either a mouse tetrad assay, indirect but important finding of this study is the forced swim test (FST), or tail suspension test role of cannabinoid receptor ligand’s binding (TST). The mouse tetrad assay measuring rectal affinity for the CB1 receptor in developing a cannabinoid receptor-based antidepressant. Page 6 of 11 A Review of the Relationship between the Endocannabinoid System and the Reduction of Depression and Anxiety 2019 Another salient takeaway from this study is that activity of the CB2 receptor may be bidirectional CBD, the non-psychoactive component of as both its agonists and antagonists displayed cannabis, exhibited antidepressant activity in the antidepressant potential. FST even though it is a “potent antagonist of CB1 In the second phase of the experiment, and CB2 receptors agonists” (El-Alfy et al., 2010, co-administration of non-effective doses of 440). This shows that there is a need for further antagonists with effective doses of agonists was investigation into the role of CB2 receptors, as performed for each receptor subtype. For both the antidepressant activity was observed through oleamide and JWH 133, immobility times in the the administration of the CB2 agonist. FST were still significantly reduced, but AM 251 and AM 630 attenuated the strength of this Endocannabinoid and Cholinergic Receptor reduction for each agonist, respectively (Kruk- Ligands Acting in Conjunction Slomka et al., 2015). While these results may be Researchers at the Medical University of expected for the CB1 receptor antagonist, the Lublin in Poland evaluated the antidepressant attenuation of antidepressant activity by the CB2 efficacy of CB1 and CB2 receptor ligands alone receptor antagonist when administered with both and in combination with cholinergic receptor the CB1 and CB2 receptor agonists is ligands ( and scopolamine), as the contradictory to its previously observed cholinergic system has previously been thought independent antidepressant effect. This directly to be involved in the antidepressant activity of reflects the complexity and subtlety of the endocannabinoids. Similar to the previous study, endocannabinoid system’s involvement in the the FST was used to evaluate depression-related reduction of depression and supports the notion responses and experimental groups were that there is a biological interaction between the designed with eight to ten mice. The cannabinoid receptor subtypes when simultaneously receptor ligands chosen were oleamide (CB1 activated. receptor agonist), AM 251 (CB1 receptor The third part of the experiment antagonist), JWH 133 (CB2 receptor agonist) and evaluated the antidepressant effects of the AM 630 (CB2 receptor antagonist). Each ligand cholinergic receptor ligands both individually, was administered via intraperitoneal injection at and in combination with both effective and non- one of four selected concentrations. The effective doses of the cannabinoid receptor cholinergic receptor ligands chosen were nicotine ligands. Both the nAChR ligand nicotine and the hydrogen tartrate (a nicotinic acetylcholine mAChR ligand scopolamine significantly receptor – nAChR agonist) and scopolamine reduced immobility times in the FST, which hydrochloride (a muscarinic acetylcholine demonstrates their antidepressant potential receptor – mAChR agonist) (Kruk-Slomka et al., (Kruk-Slomka et al., 2015). Pretreatment with 2015). cannabinoid receptor ligands had no significant In the first phase of the experiment, CB1 effect on the action of nicotine. However, the and CB2 receptor agonists and antagonists were administration of some CB compounds at non- tested independently in the FST. Oleamide and effective concentrations before a non-effective JWH 133, the cannabinoid receptor agonists, dose of scopolamine did have an antidepressant both caused a statistically significant decrease in effect (Kruk-Slomka et al., 2015). mice immobility times during the FST, which This finding is of particular significance reveals that they both exhibited an antidepressant in distinguishing the biological mechanisms effect. However, while the CB1 receptor involved in the antidepressant action of antagonist, AM 251, did not reduce immobility endocannabinoids. While endocannabinoids did times, the CB2 receptor antagonist, AM 630 (at a not improve the antidepressant effect of nicotine concentration of 0.5 mg/kg), caused a statistically (an agonist of nAChRs), it did improve the significant decrease in immobility times when antidepressant effect of scopolamine (an compared to the control (Kruk-Slomka et al., antagonist of mAChRs). This may reveal that 2015). These initial findings are intriguing endocannabinoids actually engage the activation because they suggest that the antidepressant of nAChRs, which aligns with the earlier finding that they exhibit antidepressant activity when in Page 7 of 11 Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences 2019 combination with a mAChR antagonist. From wild-type mice (Moreira et al., 2008). The study this study, the key takeaways are the complexity also tested diazepam, a compound commonly surrounding the antidepressant potential of the used to treat anxiety, to set a benchmark for CB2 receptor and the potential for synergistic reduced anxiety-like behavior of the mice in the combinations of endocannabinoids with elevated-plus maze. Although FAAH knockout cholinergic ligands or other classical mice statistically reduced anxiety-like behavior antidepressants. when compared to the wild-type mice, they still had many more entries into the enclosed arms The Potential of Endocannabinoids to (16.10 average entries) than mice treated with Reduce Anxiety diazepam (9.38 average entries). While the previous studies have mainly The researchers then tested the effect of focused on the therapeutic potential of exogenous the addition of , a CB1 receptor CB1 and CB2 receptor ligands, some research antagonist, on the behavior of the FAAH has focused more on the potential of endogenous knockout mice in the elevated-plus maze. Despite cannabinoids to reduce anxiety. A group of rimonabant treatment, the FAAH knockout mice researchers at Johannes Gutenberg-University still resided in the open arms for significantly Mainz in Germany have attempted to explore the longer than the other groups (Moreira et al., efficacy of endogenous cannabinoids by 2008). Theoretically, if CB1 receptor activation inhibiting the action of fatty acid amid hydrolase was the primary mechanism through which (FAAH). FAAH is an responsible for the endocannabinoids were reducing anxiety-like degradation of endocannabinoids like behavior, they would no longer exhibit reduced anandamide and 2-AG, and inhibitors of FAAH anxiety-like behavior upon the introduction of a have been developed to increase brain levels of CB1 receptor antagonist like rimonabant. The anandamide (Moreira et al., 2008). As an results of the FAAH knockout mice in the endocannabinoid, anandamide is distinct from elevated-plus maze displaying reduced anxiety- many synthetic cannabinoid receptor ligands that like behavior were replicated in the LDT as the operate solely through CB1 receptor activation FAAH knockout mice were drawn to the because it is a neuromodulator (Moreira et al., illuminated section of the apparatus more than the 2008). wild-type mice (Moreira et al., 2008). Although This study aimed to test whether FAAH this held true upon the addition of rimonabant, knockout mice would present reduced anxiety- there was a significant effect of the drug on the like behavior when compared to wild-type mice behavior of the FAAH knockout mice as there in the elevated-plus maze and a light dark test was reduced exploration of the lit compartment (LDT). The elevated-plus maze was designed (Moreira et al., 2008). This indicates that even if similar to the previously discussed experiment, activation of CB1 receptors is not the only and the LDT was conducted in a box divided into mechanism through which endocannabinoids a dark and lit compartment (with or without a reduce anxiety-like behavior, it is responsible for roof, respectively) (Moreira et al., 2008). The a significant portion of endocannabinoid’s percentage of entries and time spent in the open therapeutic potential in treating anxiety and arms of the elevated-plus maze and the depression. percentage of time spent in the lit compartment of In the phase of the experiment involving the LDT were measured and classified as reduced pharmacological inhibition, an FAAH inhibitor anxiety-like behavior (Moreira et al., 2008). The URB597 was administered to a treatment group experiment was conducted in two main phases, at a concentration of 1 mg/kg prior to testing in one using genetic inactivation and the other using the elevated-plus maze or LDT. Through this pharmacological inhibition of FAAH. experiment, it was discovered that the CB1 In the phase of the experiment involving receptor facilitates the anxiolytic qualities of genetic inactivation, the FAAH knockout mice FAAH inhibition (Moreira et al., 2008). were found to have reduced anxiety-like behavior Furthermore, the inhibition of FAAH by URB597 in the elevated-plus maze when compared with did not result in FAAH-inhibited mice spending more time in the lit compartment during the LDT, Page 8 of 11 A Review of the Relationship between the Endocannabinoid System and the Reduction of Depression and Anxiety 2019 which reveals a failure to reduce anxiety-like (Domschke et al., 2008, 753). Specific brain behavior when compared to wild-type mice regions including the amygdala and thalamus (Moreira et al., 2008). When comparing the two were regions of interest. phases of this study, it is apparent that the genetic From the HAM-D 21 score tracking, inactivation of FAAH has more therapeutic patients were found to respond worse to promise than the pharmacological inhibition of antidepressant treatment if they possessed the FAAH. Although the genetic inactivation of CB1 rs1049353 G allele rather than the FAAH did not reduce anxiety-like behavior as homozygous rs1049353 AA genotype effectively as the conventionally-used diazepam, (Domschke et al., 2008). This outcome is its endogenous therapeutic mechanism validates unsurprising given the prior finding that this CB1 further exploration because of its reduced side- variant had been linked to earlier depression effect profile and natural occurrence. This study stimuli. However, when the results were stratified has underscored the importance of exploration by gender, this trend was only visible in the into endocannabinoids as neuromodulators that subsample of female rather than male patients may have therapeutic mechanisms in the (Domschke et al., 2008). The gender-based treatment of anxiety beyond CB1 receptor discrepancy in the therapeutic effectiveness of activation. antidepressants because of the presence of the CB1 rs1049353 G allele reflects the repeated The Potential of Endocannabinoids to finding that females are almost twice as likely as Reduce Depression males to become depressed during their lifetime. Beyond the consideration of endogenous Specifically, this genetic polymorphism may be a and exogenous cannabinoid receptor ligands for direct mechanism of heritability that is their potential as antidepressants, other studies responsible for the higher incidence of depression have centered on studying the genetic variations in females. These results were replicated in the in the endocannabinoid systems of patients with fMRI study as individuals with the homozygous depression. One such study was conducted as a rs1049353 AA genotype had stronger brain area collaborative effort between researchers in activity to masked happy faces than those with Germany and Australia, who collected a sample the variant G allele (Domschke et al., 2008). One of 256 depression patients at the University of consideration affecting these results is that the Muenster. The Hamilton Depression Rating detrimental effect of the CB1 G allele variant on Scale (HAM-D 21) was used to track the weekly antidepressant treatment was evidenced only in self-reported depression level of each patient patients with high anxiety (Domschke et al., throughout their individualized treatment 2008). The interplay between the effects of regimen, which consisted of numerous classical genetic polymorphisms on the coding of CB1 antidepressants including citalopram, receptors and the agonists of non-variant CB1 venlafaxine, and other TCAs or MAOIs receptors on the development of anxiety must be (Domschke et al., 2008). From the 256 patients, further evaluated. Unlike the CB1 rs1049353 exclusion criteria were followed to create a subset variant, the rs12720071 genotype had no of 33 patients that would undergo a fMRI significant effect on response to antidepressant imaging study aimed at examining particular treatment in both the analysis of HAM-D 21 CB1 gene variants (Domschke et al., 2008). scores and fMRI imaging (Domschke et al., Despite the lack of previous literature on the 2008). Overall, this study has unearthed another subject, the researchers selected CB1 rs1049353 manner in which the endocannabinoid system variant because of its relation to neuronal striatal may be involved with depression and its activity in response to depression stimuli and treatment beyond just its receptor ligands. CB1 rs12720071 variant because of its relation to Research should focus on developing a more (Domschke et al., 2008). As part complete understanding of the network of of the fMRI study, the subjects “viewed endocannabinoid receptors’ genetic alternating 30 second blocks of masked happy, polymorphisms that are related to the treatment sad, angry, and neutral facial stimuli interleaved of depression. with no-face stimulus baseline blocks” Page 9 of 11 Impulse: The Premier Journal for Undergraduate Publications in the Neurosciences 2019 acetylcholine receptor antagonists like Discussion and Conclusion scopolamine (Kruk-Slomka et al., 2015). The current body of research Although the majority of research investigating the antidepressant and anxiolytic surrounding the endocannabinoid system and the properties of endocannabinoids and synthetic treatment of depression/anxiety is focused on the cannabinoid receptor ligands has revealed that types of receptor ligands best suited to create an there exists therapeutic potential for these antidepressant/anxiolytic effect, some research compounds in the treatment of disease. While has emerged studying the relation of cannabinoid anxiety and depression are distinct conditions, receptor genetics to antidepressant treatment their comorbidity has been replicated in response. Research has discovered that certain numerous research studies. While uncertainty genetic polymorphisms like the CB1 rs1049353 remains regarding the exact biological pathways G allele directly hamper the efficacy of through which cannabinoid receptors act to antidepressants (Domschke et al., 2008). reduce anxiety and/or depression, there have been Additionally, this particular genetic variant significant developments in the medical research appears to be a uniquely female issue, which may community’s understanding of the elucidate the increased incidence of depression in endocannabinoid system. CB1 receptor agonists women and provides a theoretical mechanism of and antagonists have consistently been linked to heritability for the disease. Despite these beneficial and adverse effects, respectively, on significant advancements in the field of the treatment of depression and anxiety in mouse cannabinoid receptor ligands and the treatment of behavioral studies. The role of the CB2 receptor, depression/anxiety, there are still intriguing gaps however, seems much more complex as both in our understanding that may translate into agonists and antagonists have shown beneficial viable human treatments. effects when administered independently, but More research should be performed to vary when administered in conjunction with each understand the therapeutic advantages to other or with CB1 receptor ligands. endocannabinoids versus synthetic cannabinoid While most research has prioritized the ligands. While synthetic cannabinoid ligands can development of synthetic cannabinoid receptor be varied in structure and chemical makeup to ligands for their therapeutic potential, enhance various therapeutic components like endocannabinoids (specifically anandamide) binding affinity, there are other advantages to offer a novel treatment option as endocannabinoids that should be investigated. neuromodulators beyond their role as CB1 Endocannabinoids are naturally occurring in the receptor agonists. Furthermore, endogenous human body and thus inherently pose less of a cannabinoids exist within the human body and risk to the overall health of a patient. thus avoid the significant and sometimes severe Furthermore, endocannabinoids are side-effect profiles customary of most neuromodulators that can bind with a variety of conventional antidepressants like SSRIs or other brain areas, so they are not entirely reliant TCAs. Phytocannabinoids, including delta-9- on CB1 receptor activation for their therapeutic THC, cannabidiol, and cannabichromene that are potential. Additionally, the genetic inactivation often found in strains of recreational cannabis, of FAAH may attribute greater therapeutic ability have also demonstrated potential antidepressant to endocannabinoids since CB1 receptor and anxiolytic activity in mouse studies (El-Alfy antagonists were found to have a minimal adverse et al., 2010). Much like endocannabinoids, effect on endocannabinoids’ antidepressant phytocannabinoids pose less of a detriment to activity (Moreira et al., 2008). The development health than synthetic cannabinoid ligands of a synthetic cannabinoid receptor ligand that is because they are present in naturally growing able to overcome an effective dose of a CB1 strains of cannabis. Research has also revealed receptor antagonist is a significant the potential for cannabinoid receptor ligands to pharmacological challenge that exhibit synergistic antidepressant effects with endocannabinoids naturally overcome. other compounds, specifically muscarinic Additionally, the other therapeutic mechanisms through which endocannabinoids have an Page 10 of 11 A Review of the Relationship between the Endocannabinoid System and the Reduction of Depression and Anxiety 2019 anxiolytic effect should be investigated as an essential advice on selecting and writing about alternative for patients who are unresponsive to topics in Neuropsychopharmacology. They have treatment with CB1 receptor agonists. Finally, offered me instrumental feedback on how to studies should evaluate which types of existing focus the topic of this paper on the compounds have the most potential for endocannabinoid system and investigation into synergistic effects with cannabinoid receptor its therapeutic properties. ligands. Further research is needed into the field References of genetic polymorphisms and variants in the Alger, BE (2013) Getting high on the coding of the two cannabinoid receptor subtypes. endocannabinoid system. Cerebrum 14:1-14. Given the finding that a single genetic Anderson I.M (2000) Selective serotonin polymorphism in the CB1 allele correlated to a reuptake inhibitors versus tricyclic gender-specific incidence of failed antidepressant antidepressants: a meta-analysis of efficacy treatment, this type of research has an immense and tolerability. J Affect Disord 58: 19-36. potential to evaluate mode of inheritance for Bhattacharyya S, Egerton A, Kim E, Rosso L, cannabinoid receptor genetic variants. A glaring Barros DR, Hammers A, Brammer M, complication of the discovery of cannabinoid Turkheimer F, Howes OD, McGuire P (2017) receptor polymorphisms in patients is how the Acute induction of anxiety in humans by treatment of the condition can be altered to delta-9-tetrahydrocannabinol related to improve outcomes. Moreover, studies should be amygdalar cannabinoid-1 (CB1) receptors. catered to understand how the presence of genetic Scientific Reports 7:1-15. polymorphisms in the makeup of cannabinoid Bodkin JA, Goren JL (2007) Not obsolete: receptors affects the curative prospect of continuing roles for TCAs and MAOIs. endocannabinoids and synthetic cannabinoid Psychiatr Times 24:10. receptor ligands for conditions like anxiety and Brigitta B (2002) Pathophysiology of depression depression. The role of the CB2 receptor subtype and mechanisms of treatment. Dialogues Clin needs to be thoroughly evaluated. Currently, the Neurosci 4:7-20. agonists of this receptor seem to have therapeutic Bystritsky A, Khalsa S, Cameron M, Schiffman J potential, but the antagonists vary based on the (2013) Current diagnosis and treatment of other elements of the treatment group (Domschke anxiety disorders. P & T 38: 30-38. et al., 2008). While CB1 receptor agonists seem Domschke K, Dannlowski U, Ohrmann P, to be more clearly linked to antidepressant effect, Lawford B, Bauer J, Kugel H, Heindel W, the potential of the CB2 receptor subtype should Young R, Morris P, Arolt V, Deckert J, not be ignored especially given the possibility of Suslow T, Baune BT (2008) Cannabinoid treatment-resistant depression. The breadth of receptor 1 (CNR1) gene: impact on discussed studies highlighting the possibly antidepressant treatment response and therapeutic relationship between the emotion processing in major depression. Eur endocannabinoid system and anxiety and Neuropsychopharmacol 18: 751-759. depression validates the need for thorough El-Alfy A, Ivey K, Robinson K, Ahmed S, research in the field to continue. Patients with Radwan M, Slade D, Khan I, ElSohly M, Ross severe mental disorders who do not respond to S (2010) Antidepressant-like effect of Δ9- classical antidepressants would benefit tetrahydrocannabinol and other cannabinoids tremendously from this research into the isolated from cannabis sativa L. Pharmacol prospective applications of the endocannabinoid Biochem Behav 95:434-442. system. Fergusson DM, Boden JM (2008) Cannabis use

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