A Review of the Relationship Between the Endocannabinoid System and the Reduction of Depression and Anxiety 2019
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Page 1 of 11 A Review of the Relationship between the Endocannabinoid System and the Reduction of Depression and Anxiety 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 cannabis use for medical and recreational purposes across the world has sparked interest in evaluation of the therapeutic potential of the drug. While the beneficial effects of cannabis use to treat physical pain are well-known, its efficacy as a treatment for mental health 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 antidepressants and selective serotonin 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 research studies focused on evaluating the potential of the human endocannabinoid system, which consists of two main cannabinoid receptor subtypes (CB1 and CB2). Prior studies have focused on the use of exogenous cannabinoids such as oleamide 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 – cannabinoid receptor type 1; CB2 – cannabinoid receptor type 2; delta-9- THC – delta-9-tetrahydrocannibinol; CBD – cannabidiol; 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 United States’ 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 dopamine, stimulate G protein- well as their correlation to potentially fatal health linked receptors on postsynaptic neurons 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 drugs 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-norepinephrine 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