[DRAFT] The Endocannabinoid System – Ch 7: Anxiety, Depression & The ECS

Introduction

Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Mental disorders are responsible for the largest proportion of the global burden of disease worldwide. It has been suggested that by 2030 depression will be the leading cause of disease burden globally. In this way, mood-related disorders contribute to most of the non-fatal burden of mental illness followed by anxiety-related disorders, substance abuse, and schizophrenia. They present a major medical, societal, and economic burden that has a large impact on individuals, families, and communities.

Major depressive disorder, also known simply as depression, is a mental disorder characterized by at least 2 weeks of low mood that is present across most situations. It is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause. Major depressive disorder can negatively affect a person’s personal, work, or school life, as well as sleeping and eating habits, and general health. The probability of suffering from depression at some point during one’s lifespan is up to 15% for men and 30% for women. There are two main challenges to fighting against depression. First, we still poorly understand its neurobiological and pathological bases. Second, there needs to be more effective antidepressant drugs overcoming the therapeutic lag between drug administration and the onset of clinical improvement, the lack of response in some patients, and safety/tolerability issues. It is therefore of great importance to identify new fast-acting antidepressants.

On the other hand, pathological anxiety is one of the most common types of mental illness, globally ranked 33rd in its prevalence and the 9th cause of years lived with a disability according to the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. Anxiety disorders are a group of mental disorders characterized by significant feelings of anxiety and fear. These feelings may cause physical symptoms, such as a fast heart rate and shakiness. Anxiolytic drugs such as benzodiazepines produce rapid effects, but their long-term use causes severe adverse effects, such as drowsiness, dizziness, and decreased alertness and concentration.

The most commonly reported reason for cannabis use by the majority of users worldwide is its relaxing effect, suggesting that cannabinoid signaling could play a role in the control of anxiety and depression. Indeed, a number of emotions and behaviors, such as fear, anxiety, depression, stress-coping, and reward-driven behaviors are critically modulated by the ECS. In recent years, the endocannabinoid system (ECS) has been recently recognized as a prominent promoter of emotional homeostasis, mediating the effects of different environmental signals including rewarding and stressing stimuli. The ECS modulates the rewarding effects of environmental stimuli, influencing synaptic transmission in the dopaminergic projections to the limbic system, and mediates the neurophysiological and behavioral consequences of stress. The ECS influences the activity of multiple brain areas involved in the regulation of the hypothalamic-pituitary-adrenal system, mood, anxiety, and other related behaviors (i.e. extinction of fear learning, reward…). Within distinct cerebral regions, eCB signaling can differentially modulate the activity of multiple cell types (neuronal subtypes, astrocytes, and microglia) and in turn execute context-related alterations in synaptic transmission, thereby regulating behavioral outputs. The complex influences of the ECS on both the environmental and internal stimuli processing, make the cannabinoid-based drugs an appealing option to treat different psychiatric conditions.

Literature

A review by the Fourth Military Medical University in China and the University of Ottawa Institute of Mental Health Research at the Royal in Canada examined the evidence for eCB influence in anxiety- and stress-related dysfunctions, such as depression, and the research on other neural circuits. They found that CB1R shows particularly dense expression in regions with known involvement in fear, anxiety, and stress, including the hippocampus, prefrontal cortex (PFC), bed nucleus of the stria terminalis, basolateral amygdala (BLA), central amygdala, and various hypothalamic nuclei. Specifically, eCB may help reverse the acute and chronic stress response; it may produce antidepressant physiological changes, including neurogenesis and synaptic plasticity; people with depression have relatively lower eCB levels. This makes AEA a good candidate to treat depression induced by acute stress. Thus, the stress-induced downregulation of CB1R signaling in brain regions is of vital importance for the regulation of emotional processes, such as depression.

Moreover, they showed that the eCB system participates in the bidirectional regulation of anxiety circuits and behavior. First, they found that exogenous cannabinoids such as Δ9 -THC and synthetic cannabinoids influence anxiety‐like behavior in a biphasic manner, with low and high doses exerting anxiolytic and anxiogenic states, respectively. Second, the CB1Rs on cortical glutamatergic and GABAergic neurons exert opposing control on anxiety‐like behaviors. Third, the Global CB1R knockout results in increased anxiety-like behavior. Fourth, the deletion of the 2-AG MAGL leads to a significantly increased anxiety-like behavior. Fifth, the overexpression of 2-AG hydrolyzyme in the hippocampal glutamatergic neurons led to increased anxiety-like behavior, whereas pharmacological inhibition of 2-AG hydrolyzyme produces an anxiolytic effect. Sixth, the genetic knockout or pharmacological inhibition of the AEA hydrolytic enzyme FAAH produces anxiolytic effects without the side effects of marijuana. Finally, the substrate-selective COX-2 inhibitors may inhibit the oxygenation of 2-AG and AEA and produce anxiolytic effects in preclinical models.

Likewise, a review by the Tor Vergata University in Italy went over the multifaceted effects of cannabinoids with the aim to understand how to boost their therapeutic use in anxiety and depression treatment. They found that the clinical effectiveness of different antidepressants is mediated by modulation of ECS activity in specific brain regions, including the hypothalamus, the amygdala, and the hippocampus. In particular, chronic treatment with tricyclic antidepressants was associated with increased CB1R density in the hippocampus and hypothalamus and reduced hypothalamic-pituitary-adrenal (HPA) axis activation in response to stressing stimuli. Moreover, in patients with major depression, there are reduced circulating levels of both 2-AG and AEA and chronic treatment with CB1R antagonists has been associated with an increased incidence of anxiety and depression. In particular, the CB1R antagonist rimonabant introduced for smoking cessation and to treat obesity was suspended following several reports of severe mood depressant action. Interestingly, in patients with major depression, genetic variations of the CNR1 (cannabis receptor type 1) have been associated with depressive symptoms and with major depression, influence the response to antidepressant treatment, interact with previous negative experiences increasing the susceptibility to depression, and affect responsiveness of subcortical structures, including the amygdala and striatum, to socially rewarding stimuli.

Moreover, they highlighted the relationship between the immune response and mood disturbances since it has been shown that inflammatory signals and environmental stimuli interact with the ECS to produce mood changes. In different inflammatory conditions, pro-inflammatory mediators could induce anxiety, anhedonia, social withdrawal, fatigue, and sleep disturbances, defined as “sickness behavior”. Accordingly, systemic administration of pro-inflammatory agents is able to promote the activation of microglial cells in the hippocampus and stimulate the release of pro-inflammatory cytokines in the CNS and is associated with depression and anxiety. Thus, making the ECS a candidate to treat the anxiety through this approach.

Finally, a collaboration between the University of the Basque Country UPV/EHU, the Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, the Universidad de Cantabria and the Biocruces Health Research Institute in Spain summarized data obtained from human studies providing evidence about the role of the different ECS components (endocannabinoids, metabolizing/synthesizing enzymes and cannabinoid receptors) in the pathophysiology and treatment of several psychiatric disorders, with a focus on results from postmortem and living human brain studies. They first found that augmented ECS signaling was usually followed by reduced conditioned fear and anxiety, whereas the opposite effect is observed when it is inhibited. Human studies have corroborated the existence of an altered ECS activity associated with major depression. The CB1 receptor density and mRNA are increased in the dorsolateral prefrontal cortex of patients with major depression, in parallel to CB1 receptor functionality. Furthermore, neuroimaging studies in non-cannabis users show that the administration of THC produces a reduced activation of some brain areas in response to negative content. Conversely, there is increased activation in response to a positive content, mediated by the activation of areas such as prefrontal and occipital cortices, amygdala, hippocampus, and orbitofrontal gyrus, which is associated with a reduction in the negative attentional bias, and the potentiation of positive attentional bias. This type of study has also shown that the activation of cannabinoid receptors leads to morphological changes, such as the reduction in white matter (WM) observed in cannabis users negatively correlates with the severity of the depressive disorder. This decrease in WM volume has been associated with the presence of cannabinoid receptors in oligodendrocytes, the myelin-forming cells.

On the other hand, few neurochemical, molecular genetics and neuroimaging studies suggest a potential link between dysregulation of the endocannabinoid signaling and anxiety-related behavior in both healthy and patients with mental disorders in which anxiety is a core symptom (PTSD, social phobia, agoraphobia, etc…). Most of the findings in depression and anxiety are related to the expression and/or functionality of CB1 receptors and FAAH in brain areas belonging to the amygdala-hippocampal-cortico-striatal neural circuit, especially the frontal cortex in depression and the amygdala in anxiety disorders. Pharmacological strategies that reduce the activity of either FAAH or MAGL have been reported to reduce anxiety-like behaviors in rodents and humans; however, dual FAAH/MAGL inhibitors did not reduce stress-related affective dysfunction regardless of treatment timing.

Limitations

It should be considered that a number of factors may contribute to the lack of clear findings. It has been observed that many of the clinical studies were considered at high risk of bias, generally for incomplete reports of outcome measures and for an inadequate blinding procedure. In addition, clinical studies mainly explored the effects of synthetic principles, and studies exploring the effects of cannabis are limited. Moreover, some of the studies are based on pre-clinical trials.

Conclusions

Emotional homeostasis is crucially modulated by the activity of the ECS. The mechanisms underlying the interaction between ECS and mood are different and include the modulation of activity in limbic areas involved in reward processing, regulation of other neurotransmitters (i.e., noradrenaline, NA; DA; 5-HT), and HPA activation in the stress response. The eCB system is present in many brain circuits that are well known to regulate anxiety and depression processes. Moreover, there seems to be an apparent yin–yang relationship between AEA and 2-AG, with both molecules providing a stress-inhibitory effect, but the reduction of AEA is responsible for the initiation and manifestation of the effects of stress, whereas the increase of 2-AG is responsible for tempering and terminating the stress response. Together with anatomical descriptions and functional evidence, eCB signaling might modulate synaptic activity at many nuclei of these circuits.

Although ample experimental evidence shows beneficial effects of ECS modulation on mood, scarce clinical indication limits the use of cannabis-based treatments. To better define the possible clinical indications of cannabinoid-based drugs in psychiatry, a number of issues should be better addressed, including genetic variability and psychosocial factors possibly affecting the individual response. In particular, better knowledge of the multifaceted effects of cannabinoids could help to understand how to boost their therapeutic use in anxiety and depression treatment. A specific confounding factor that limits the clinical evidence supporting the beneficial effects of cannabinoids on mood is the difficulty in controlling the placebo effect. In clinical trials evaluating the efficacy of antidepressant medications, it has been shown that the placebo effect could be responsible for at least one-half of the beneficial effect representing a relevant confounding factor. Indeed, as ECS mediates both the antidepressant effect of drugs and the placebo response, patients responding to antidepressant drugs may also show a marked placebo response. Finally, concerns about the risks associated with cannabis use have limited the clinical indications of medical marijuana. In particular, acute cannabis use has also been associated with worsening of anxiety. It has been proposed that chronic consumption could be associated with an increased risk of psychosis, cognitive impairment, and addictiveness in predisposed subjects.

An understanding of the underlying neural cell populations and neural circuit regulation will enable the development of therapeutic strategies to mitigate behavioral maladaptation and provide insight into the influence of eCB on the neural circuits involved in anxiety and depression. How the eCB system regulates anxiety and depression has been studied for a long time. These studies mentioned above raise strong hopes not only for a better understanding of the behavioral processes but also for future therapy to rescue these dysfunctions. In the future, by integrating the cutting-edge research methods, the causal links between the eCB system-meditated synaptic plasticity/electrophysiological modulations and behavioral outcomes will be well revealed. Also, future clinical trials should be designed to explore specific outcome measures, reduce individual variability, and to consider the placebo response. In the last years, the ample diffusion of smoked or vaporized cannabis for recreational and therapeutic purposes has not been accompanied by measures aimed at promoting information about medical marijuana use. In this view, it is important to design specific interventions to overcome the gap between preclinical studies and clinical evidence on the potential therapeutic use of cannabinoids. The advance in this field, together with the translational preclinical research is opening an attractive research scenario for the development of promising new pharmacological strategies based on drugs targeting the ECS to treat mental disorders.

I. Ibarra-Lecue, F. Pilar-Cuéllar, C. Muguruza, E. Florensa-Zanuy, A. Díaz, L. Urigüen, E. Castro, A. Pazos, L.F. Callado, The endocannabinoid system in mental disorders: Evidence from human brain studies, Biochemical Pharmacology (2018), doi: https://doi.org/10.1016/j.bcp.2018.07.009

Stampanoni Bassi M, Gilio L, Maffei P, Dolcetti E, Bruno A, Buttari F, Centonze D and Iezzi E (2018) Exploiting the Multifaceted Effects of Cannabinoids on Mood to Boost Their Therapeutic Use Against Anxiety and Depression. Front. Mol. Neurosci. 11:424. doi: 10.3389/fnmol.2018.00424

Yin, A., Wang, F., & Zhang, X. (2018). Integrating endocannabinoid signaling in the regulation of anxiety and depression. Acta Pharmacologica Sinica. doi:10.1038/s41401-018-0051-5